−Removed: We are a discovery through late-stage development biopharmaceutical company focused on peptide therapeutics.
−Removed: Our clinical programs fall into two broad categories of diseases:
−Removed: (i) hematology and blood disorders, and (ii) inflammatory and immunomodulatory (“I&I”) diseases.
−Removed: Two novel peptides derived from our proprietary discovery technology platform, rusfertide and icotrokinra (formerly known as JNJ-2113), are currently in advanced Phase 3 clinical development, with New Drug Application (“NDA”) submissions to the U.S.
−Removed: Food and Drug Administration (“FDA”) potentially in 2025.
−Removed: Rusfertide, an injectable mimetic of the natural hormone hepcidin, is currently in Phase 3 development for treatment of the rare blood disorder polycythemia vera (“PV”).
−Removed: Rusfertide is being co-developed and will be co-commercialized with Takeda Pharmaceuticals, Inc.
−Removed: (“Takeda”) and the Company remains primarily responsible for development through NDA filing.
−Removed: Icotrokinra is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (“IL-23R”) and is licensed to J&J Innovative Medicines (“JNJ”), formerly Janssen Biotech, Inc.
−Removed: Following icotrokinra’s joint discovery by us and JNJ scientists pursuant to our IL-23R collaboration, we were primarily responsible for the development of icotrokinra through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond.
−Removed: We also have a number of pre-clinical stage oral drug discovery programs to address clinically and commercially validated targets, including IL-17 oral peptide antagonist PN-881, an oral metabolic/obesity peptide program, and an oral hepcidin mimetic/ferroportin blocker program.
−Removed: 2024 Key Highlights
−Removed: Worldwide License and Collaboration Agreement for Rusfertide with Takeda
−Removed: ● On January 31, 2024, we and Takeda announced a worldwide license and collaboration agreement for rusfertide.
−Removed: We received an upfront cash payment of $300.0 million in April 2024, and we are eligible to receive up to $330.0 million in development, regulatory, and sales milestones, for a potential deal value of up to $630.0 million, as well as an equal share of profits and losses in the U.S.
−Removed: and royalties on net sales outside the U.S.
−Removed: ● Under the terms of the agreement, we have the right to opt-out of the 50:50 profit share.
−Removed: In that event, we would be eligible to receive additional cash payments of up to $400.0 million and enhanced milestones of up to $975.0 million, as well as royalties on worldwide net sales.
−Removed: Takeda would maintain full ex-U.S.
−Removed: rights under either scenario.
−Removed: Two articles published in the New England Journal of Medicine (“NEJM”) in February 2024
−Removed: ● On February 7, 2024, the icotrokinra Phase 2b FRONTIER 1 trial results in adults living with moderate-to-severe plaque psoriasis were published in the NEJM.
−Removed: ● On February 21, 2024, the complete Phase 2 REVIVE trial results for rusfertide, including efficacy and safety data, were published in the NEJM.
−Removed: Addition to S&P SmallCap 600 Index
−Removed: We joined the S&P SmallCap 600 Index on July 3, 2024.
−Removed: Positive Phase 3 topline results from Phase 3 ICONIC studies of icotrokinra in plaque psoriasis
−Removed: ● On November 18, 2024, we announced that in the ICONIC-LEAD study, once-daily icotrokinra showed significant skin clearance versus placebo in adults and adolescents with moderate to severe plaque psoriasis.
−Removed: At week 16, nearly two-thirds (64.7%) of patients treated with icotrokinra achieved Investigator’s Global Assessment (“IGA”) scores of 0 or 1 (clear or almost clear skin), and 49.6% achieved PASI 90 (90% improvement in skin lesions as measured by the Psoriasis Area and Severity Index (“PASI”)), compared to 8.3% and 4.4% on placebo, respectively.
−Removed: ● Further increases in response rates continued to be observed at week 24, with 74.1% of patients treated with icotrokinra achieving IGA scores of 0 or 1, and 64.9% achieving PASI 90.
−Removed: Safety data was found to be consistent with the Phase 2 FRONTIER 1 and 2 studies.
−Removed: A similar proportion of patients experienced adverse events between icotrokinra and placebo, with 49.3% and 49.1% of participants, respectively, experiencing a treatment-emergent adverse event (“TEAE”) at week 16.
−Removed: ● In addition, positive topline results from the Phase 3 ICONIC-TOTAL study showed that once-daily icotrokinra met the primary endpoint of IGA of 0 or 1 at week 16 compared to placebo.
−Removed: Nomination of PN-881, a potential best-in-class oral peptide IL-17 antagonist development candidate;
−Removed: additional discovery programs announced
−Removed: ● On November 21, 2024, we announced the nomination of PN-881 following extensive preclinical studies, including oral stability, potency, tissue distribution, and pharmacokinetics measurements, and evaluation in immunologic pharmacodynamics and preclinical efficacy models.
−Removed: PN-881 showed in vitro blockade of IL-17 AA homodimer, FF homodimer and AF heterodimer.
−Removed: It showed approximately 100-fold greater potency than secukinumab, and similar potency to the most potent approved antibody drugs and nanobody therapeutics currently in development.
−Removed: ● We expect to nominate an oral development candidate in the hepcidin mechanism-based hematology program in the fourth quarter of 2025, and an oral peptide-based development candidate in the metabolic/obesity program in the second quarter of 2025.
−Removed: Achievement of an amended $165.0 million milestone
−Removed: ● Under the terms of the icotrokinra license and collaboration agreement with J&J, as amended in November 2024, we earned $165.0 million in milestone payments during the fourth quarter of 2024.
−Removed: ● The $165.0 million payment was received in January 2025, and we remain eligible for up to $630.0 million in future development and sales milestone payments, and tiered royalties of 6-10% on worldwide net sales.
−Removed: The 10% royalty tier applies to net worldwide sales of $4 billion or more.
−Removed: Significantly enhanced cash resources
−Removed: We ended fiscal 2024 with cash, cash equivalents and marketable securities of approximately $559.2 million, a significant increase from cash, cash equivalents and marketable securities of approximately $341.6 million as of December 31, 2023.
−Removed: Our Product Pipeline
−Removed: Rusfertide is currently in Phase 3 development for the treatment of PV.
−Removed: VERIFY (ClinicalTrials.gov identifier NCT05210790) is a global double-blind, placebo-controlled Phase 3 clinical trial of rusfertide in PV for approximately 250 patients.
−Removed: The trial evaluates the efficacy, symptom burden and safety of once-weekly, subcutaneously self-administered rusfertide in patients with uncontrolled hematocrit who are phlebotomy dependent despite standard of care treatment.
−Removed: The trial enrolled patients across North and South America, Europe, Asia and Australia.
−Removed: We expect to announce top-line data for the trial’s 32-week primary efficacy endpoint in March 2025, potentially leading to an NDA filing in the fourth quarter of 2025.
−Removed: Our rusfertide Phase 2 clinical trials include the following:
−Removed: ● REVIVE (NCT04057040) – A Phase 2 proof of concept (“POC”) trial, was initiated in the fourth quarter of 2019.
−Removed: We completed enrollment of patients in the first quarter of 2022 and 70 patients were enrolled through the end of the randomized withdrawal portion of the trial, which was completed during the first quarter of 2023 and is continuing in an ongoing open-label extension (“OLE”);
−Removed: ● THRIVE (NCT06033586) – A Phase 2 long-term OLE for REVIVE patients on years three through five of treatment;
−Removed: ● PACIFIC (NCT04767802) – Another Phase 2 trial for rusfertide for patients diagnosed with PV and with routinely elevated hematocrit levels (>48%), was initiated during the first quarter of 2021, and the 52-week trial was completed during the second quarter of 2023.
−Removed: Final results from the REVIVE trial presented at the American Society of Hematology (“ASH”) 2024 Annual Meeting in December 2024 showed that 54% of patients with PV experienced more than 2.5 years of durable hematocrit control (<45%), decreased phlebotomy use, long-term tolerability and improvements in patient-reported outcomes.
−Removed: In January 2024, we entered into a worldwide license and collaboration agreement for rusfertide with Takeda (the “Takeda Collaboration Agreement”).
−Removed: We are primarily responsible for the development of rusfertide through a potential
−Removed: Under the terms of the agreement, we received a one-time, non-refundable upfront payment of $300.0 million in April 2024, and we are eligible to receive additional worldwide development, regulatory and commercial milestone payments for rusfertide of up to $330.0 million, inclusive of the following potential upcoming milestones:
−Removed: ● $25.0 million upon successful achievement of the primary endpoint in the Phase 3 VERIFY trial for rusfertide in PV;
−Removed: ● $50.0 million upon FDA approval of an NDA for rusfertide in PV (or $75.0 million if we exercise our full right to opt-out of the 50:50 U.S.
−Removed: profit and loss sharing arrangement).
−Removed: We are also eligible to receive tiered royalties from 10% to 17% on ex-U.S.
−Removed: net sales of rusfertide and other specified second-generation injectable hepcidin memetic compounds (the “Licensed Products”).
−Removed: We and Takeda will also share equally in profits and losses (50% to us and 50% to Takeda) of the Licensed Products in the United States, if approved.
−Removed: See Note 3 to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for further details related to the agreement, including our right to opt-out of the 50:50 U.S.
−Removed: profit and loss sharing arrangement.
−Removed: Our IL-23R antagonist compound icotrokinra, licensed to J&J, is an orally delivered drug that is designed to block biological pathways currently targeted by marketed injectable antibody drugs.
−Removed: Our orally stable peptide approach may offer a targeted therapeutic approach for gastrointestinal and systemic compartments as needed.
−Removed: We believe that, compared to antibody drugs, icotrokinra has the potential to provide clinical improvement in an oral medication with increased convenience and compliance and the opportunity for the earlier introduction of targeted oral therapy.
−Removed: JNJ has initiated the following icotrokinra trials:
−Removed: ● ICONIC-LEAD (NCT06095115) – A 684-patient randomized, controlled Phase 3 trial to evaluate the safety and efficacy of icotrokinra compared with placebo in participants with moderate-to-severe plaque psoriasis, with PASI-90 and IGA scores of 0 (clear) or 1 (almost clear) as co-primary endpoints;
−Removed: ● ICONIC-TOTAL (NCT06095102) – A 311-patient randomized, controlled Phase 3 trial to evaluate the efficacy and safety of icotrokinra compared with placebo for the treatment of plaque psoriasis in participants with at least moderate severity affecting special areas (scalp, genital, and/or palms of the hands and soles of the feet) with overall IGA scores of 0 or 1 as the primary endpoint;
−Removed: ● ICONIC-ADVANCE 1 (NCT06143878) – A 774-patient randomized, controlled Phase 3 trial to evaluate the effectiveness of icotrokinra in participants with moderate-to-severe plaque psoriasis compared to placebo and Sotyktu® (“deucravacitinib”).
−Removed: The trial’s primary co-endpoints are PASI-90 and IGA scores of 0 or 1;
−Removed: ● ICONIC-ADVANCE 2 (NCT06220604) – A 731-patient Phase 3 trial similarly designed to ICONIC ADVANCE 1 in participants with moderate-to-severe plaque psoriasis;
−Removed: ● Pustular/Erythrodermic Psoriasis (NCT06295692) – A 19-patient open label Phase 3 trial to evaluate the effectiveness of icotrokinra in participants with pustular or erythrodermic psoriasis;
−Removed: ● ICONIC-PsA 2 (NCT06807424) – A 750-patient randomized, controlled Phase 3 trial to evaluate the efficacy and safety of icotrokinra compared with placebo in biologic-experienced patients with active psoriatic arthritis (“PsA”);
−Removed: ● ANTHEM-UC (NCT06049017) – A 252-patient randomized, controlled Phase 2b trial to evaluate the safety and effectiveness of icotrokinra compared with placebo in participants with moderate-to-severely active ulcerative colitis (“UC”).
−Removed: In the fourth quarter of 2024, we announced positive topline results for the ICONIC-LEAD and ICONIC-TOTAL Phase 3 trials.
−Removed: In the ICONIC-LEAD trial, once daily icotrokinra showed significant skin clearance versus placebo in adults and adolescents with moderate to-severe plaque psoriasis.
−Removed: At week 16, nearly two-thirds (64.7%) of patients
−Removed: treated with icotrokinra achieved IGA scores of 0 or 1 and 49.6% achieved PASI-90, compared to 8.3% and 4.4% on placebo, respectively.
−Removed: In addition, topline results from the Phase 3 ICONIC-TOTAL trial showed that once daily icotrokinra met the primary endpoint of IGA scores of 0 or 1 at week 16 as compared to placebo.
−Removed: Comprehensive results from both ICONIC-LEAD and ICONIC-TOTAL are expected to be presented at upcoming medical congresses and shared with health authorities in planned submissions.
−Removed: Topline results for the ANTHEM trial are expected in the first quarter of 2025.
−Removed: Topline results for the ICONIC-ADVANCE 1, ICONIC-ADVANCE 2, and pustular/erythrodermic psoriasis trials are expected in the second quarter of 2025.
−Removed: On July 27, 2021, we entered into an Amended and Restated License and Collaboration Agreement with JNJ, which amended and restated the License and Collaboration Agreement, effective July 13, 2017, by and between the Company and JNJ, as amended by the first amendment, effective May 7, 2019 (together, the “JNJ License and Collaboration Agreement”) for the development and commercialization of icotrokinra.
−Removed: During the fourth quarter of 2023, we earned a $50.0 million milestone payment in connection with the dosing of the third patient in the ICONIC-TOTAL Phase 3 clinical trial of icotrokinra in patients with moderate-to-severe psoriasis and a $10.0 million milestone payment upon the dosing of the third patient in the ANTHEM Phase 2b trial in patients with moderately-to-severely active UC.
−Removed: The JNJ License and Collaboration Agreement was further amended in November 2024 to:
−Removed: ● increase the milestone payment for a Phase 3 clinical trial of any licensed product for any indication meeting its primary endpoint by $50.0 million, from $115.0 million to $165.0 million;
−Removed: ● eliminate the $35.0 million milestone payment previously due for the acceptance of an NDA filing by the FDA for a licensed product for any indication;
−Removed: ● eliminate the $15.0 million milestone payment previously due for the dosing of the third patient in the first Phase 3 clinical trial of a licensed product for a second indication.
−Removed: We earned the $165.0 million milestone payment described above during the fourth quarter of 2024.
−Removed: We have earned a total of $337.5 million in nonrefundable payments from JNJ from 2017 through December 31, 2024.
−Removed: We are eligible to receive up to $630.0 million in future development and sales milestone payments, inclusive of the following potential upcoming milestones:
−Removed: ● $50.0 million milestone upon approval of an NDA for icotrokinra in any indication;
−Removed: ● $25.0 million milestone upon the acceptance of an NDA filing by the FDA for icotrokinra in a second indication;
−Removed: ● $45.0 million milestone upon the approval of an NDA for icotrokinra in a second indication.
−Removed: We also remain eligible to receive upward tiering royalties on net product sales at percentages ranging from 6% percent to 10% percent, with 10% percent applicable for net sales over $4.0 billion.
−Removed: See Note 3 to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for additional information.
−Removed: In the fourth quarter of 2024, we announced the selection of PN-881, a potential best-in-class oral peptide IL-17 antagonist, as a development candidate for the treatment of immune-mediated skin diseases.
−Removed: PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), which may offer potential treatment options for h idradenitis suppurativa (“HS”), spondyloarthritis, plaque psoriasis and psoriatic arthritis (“PsA”).
−Removed: Investigational New Drug (“IND”), or foreign equivalent, enabling studies are ongoing, and we expect to initiate a PN-881 Phase 1 study in the fourth quarter of 2025.
−Removed: Discovery Platform
−Removed: Our clinical and pre-clinical assets are all derived from our proprietary discovery platform.
−Removed: Our platform enables us to engineer novel, structurally constrained peptides that are designed to retain key advantages of both orally delivered small molecules and injectable antibody drugs while overcoming many of their limitations as therapeutic agents.
−Removed: Importantly, constrained peptides can be designed to potentially alleviate the fundamental instability inherent in traditional peptides to allow different delivery forms, such as oral, subcutaneous, intravenous, and rectal.
−Removed: Our discovery pipeline has strategically focused on (i) hematology and blood disorders, (ii) I&I diseases and (iii) metabolic diseases, including obesity.
−Removed: We have a pre-clinical stage program to identify an orally administered hepcidin mimetic/ferroportin blocker, which we believe to be complementary to the injectable rusfertide for offering the best treatment options for PV and other potential erythropoietic and iron imbalance disorders, and we expect to nominate a development candidate in the fourth quarter of 2025.
−Removed: We also have an oral peptide-based metabolic/obesity program and expect to nominate a development candidate in the second quarter of 2025.
−Removed: AN INJECTABLE HEPCIDIN MIMETIC
−Removed: Rusfertide, an injectable hepcidin mimetic, was discovered through our peptide technology platform.
−Removed: Hepcidin is a natural hormone that regulates iron metabolism.
−Removed: We are developing rusfertide for the treatment of PV.
−Removed: Polycythemia Vera
−Removed: PV is a rare myeloproliferative neoplasm that is typically associated with a Janus Kinase (“JAK”) 2 mutation.
−Removed: PV is primarily characterized by the overproduction of red blood cells (“RBCs”), which contributes to an elevated risk of cardiovascular and thrombotic events, such as heart attack and stroke.
−Removed: PV is also associated with a risk of disease progression to myelofibrosis or leukemia.
−Removed: According to National Comprehensive Cancer Network (“NCCN”) guidelines, age and thrombosis history determine a patient’s risk classification as either low-risk or high-risk.
−Removed: Regardless of risk, treatment guidelines for PV consistently emphasize the importance of controlling the patient’s hematocrit (RBCs as a percentage of whole blood) below 45% to reduce thrombotic risk.
−Removed: Early-stage patients are typically treated with low dose aspirin and therapeutic phlebotomy.
−Removed: Hydroxyurea may also be used alone or in combination with phlebotomy.
−Removed: At later stages, patients may receive interferons, marketed as Besremi® or Pegasys®, or ruxolitinib, a JAK inhibitor marketed as Jakafi®.
−Removed: Cytoreductive therapies such as hydroxyurea, interferons and ruxolitinib impact all cell lines and can have challenging side effect profiles associated with their cytoreductive mechanisms.
−Removed: We believe there are substantial PV patient groups that could benefit from a new non-cytoreductive therapeutic option which specifically targets RBCs.
−Removed: Although NCCN guidelines state that hematocrit levels should be maintained below 45% to reduce thrombotic risk, analysis of a large medical claims database indicated that 78% of treated PV patients did not maintain hematocrit control below 45%.
−Removed: These findings showed that current therapies do not offer adequate hematocrit control, highlighting a significant unmet need in the United States alone where patients may have an elevated risk of cardiovascular and thrombotic events.
−Removed: There are approximately 155,000 diagnosed (approximately 78,000 treated) patients living in the United States, with a similar number in Europe, representing an estimated market opportunity of approximately $1.0 billion to $2.0 billion.
−Removed: Patients are typically diagnosed between the ages of 50 and 70, and median survival is approximately 14 years.
−Removed: Approximately 55% of treated PV patients receive frequent phlebotomy and high doses of hydroxyurea, which can cause undue burden to the patient.
−Removed: Additionally, approximately 16% of patients experience a thrombotic event while receiving treatment(s) for PV.
−Removed: We believe rusfertide can potentially benefit a broad spectrum of patients across the continuum of care, either as monotherapy or in combination with other cytoreductive therapies.
−Removed: We believe that rusfertide has the potential to provide a substantial benefit to patients by offering a treatment focused on managing hematocrit in a consistent and predictable manner, dramatically decreasing the need for phlebotomy.
−Removed: Rusfertide is a non-cytoreductive mimetic of the natural hormone hepcidin, the master regulator of iron homeostasis in the body.
−Removed: Since high RBC production consumes iron stores, PV can cause iron deficiency, which is often exacerbated by phlebotomy.
−Removed: Rusfertide has a unique iron regulatory mechanism, which data from our Phase 2 REVIVE trial suggests allows for persistent control of hematocrit without causing iron deficiency.
−Removed: Rusfertide acts by redistributing iron away from the bone marrow, where iron is essential for RBC production, thereby limiting excess RBC production while still providing sufficient iron levels to support other normal cellular and organ functions.
−Removed: Cancers are common in PV patients.
−Removed: A retrospective analysis presented at the ASH 2023 Annual Meeting in December 2023 on the incidence of cancers in PV patients not treated with rusfertide demonstrated the heightened underlying cancer risk in this population, particularly among those treated with hydroxyurea.
−Removed: Additionally, the majority of patients with prior TEAEs, who are at highest risk of developing a TEAE, did not experience recurrent TEAEs while on rusfertide.
−Removed: The mechanisms contributing to the increased risk of cancers in PV patients are not well understood.
−Removed: However, the subset of PV patients treated with hydroxyurea in this study of real-world claims data had nearly twice the rate of cancers compared to phlebotomy-only treated patients.
−Removed: Clinical Development of Rusfertide in PV
−Removed: In the fourth quarter of 2019, we initiated REVIVE, a Phase 2 trial of rusfertide in PV designed to evaluate safety and preliminary efficacy in patients requiring phlebotomy (“PHL”).
−Removed: The REVIVE trial was expected to enroll approximately 60 patients and consisted of a 16-week open-label dose finding stage every 4 weeks from 10 mg to 80 mg and a 12-week maintenance period at doses which generate desired hematocrit levels, followed by a 12-week randomized and blinded withdrawal stage.
−Removed: The endpoints of this clinical POC trial include measurement of blood parameters (hematocrit and hemoglobin levels), reductions or delay in phlebotomy requirements, and improvements in quality-of-life symptoms.
−Removed: We initiated THRIVE, a Phase 2 long-term extension trial, to monitor long-term safety and benefits of rusfertide for REVIVE patients on years three through five of treatment.
−Removed: REVIVE and THRIVE:
−Removed: Rusfertide Phase 2 PV Trial Design
−Removed: Preliminary results showed that the vast majority of patients treated with rusfertide in the REVIVE clinical trial were able to eliminate therapeutic phlebotomies and maintain a target hematocrit level of less than 45 percent.
−Removed: Treatment with rusfertide was also shown to reverse iron deficiency, an important side effect of regular therapeutic phlebotomies as a treatment for PV.
−Removed: Preliminary results indicated that rusfertide therapy resulted in rapid, sustained and durable hematocrit control without clinically meaningful changes in white blood cell and platelet counts.
−Removed: Rusfertide demonstrated similar efficacy in all categories of patients, independent of the PV patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib.
−Removed: In March 2023, we announced positive topline results from the blinded, placebo-controlled, randomized withdrawal portion of the REVIVE trial.
−Removed: Subjects receiving rusfertide achieved statistically significant improvements versus placebo in the trial’s primary endpoint.
−Removed: The double-blind, placebo-controlled, 12-week randomized withdrawal portion was included as Part 2 of the REVIVE trial to evaluate rusfertide in PV patients with frequent phlebotomy requirements.
−Removed: In the REVIVE trial, subjects were initially enrolled in the 28-week open label dose-titration and efficacy evaluation Part 1 of the trial, followed by 1:1 randomization of 53 subjects to placebo versus rusfertide therapy for a subsequent duration of 12 weeks.
−Removed: More subjects receiving rusfertide during the blinded randomized withdrawal portion
−Removed: of the REVIVE trial were responders compared with placebo (69.2% versus 18.5%, p=0.0003).
−Removed: A trial subject was defined as a responder if the subject completed 12 weeks of double-blind treatment while maintaining hematocrit control without phlebotomy eligibility and without phlebotomy.
−Removed: During the 12 weeks of the blinded, randomized withdrawal, 92.3% of subjects on rusfertide (24 out of 26) were not phlebotomized.
−Removed: In addition, in subjects with moderate or severe Myeloproliferative Neoplasm-Symptom Assessment Form (“MPN-SAF”) symptom scores at baseline, the change from baseline was statistically significant in fatigue, problems with concentration, inactivity and itching during the 28-week open label Part 1 of the trial.
−Removed: Meaningful comparison of symptoms assessments in Part 2 are not possible since a majority of subjects randomized to placebo discontinued prior to the 12-week assessment of MPN-SAF symptoms.
−Removed: Rusfertide continued to be generally well tolerated in the REVIVE trial, with localized ISRs comprising the majority of reported adverse events.
−Removed: No new safety signals were observed in safety data disclosed in connection with the Part 2 efficacy results, relative to the safety data from the REVIVE trial presented at the December 2022 ASH Annual Meeting, which indicated that 84% of TEAEs were Grade 2 or below.
−Removed: 16% of patients experienced Grade 3 TEAEs and there were no Grade 4 TEAEs.
−Removed: In December 2023, we presented two-year follow up data from patients in the Phase 2 REVIVE trial who continued into the OLE at the ASH 2023 Annual Meeting.
−Removed: The Phase 2 trial consisted of three parts including 70 patients in the dose-finding Part 1 (28 weeks), 59 patients in the placebo-controlled, randomized withdrawal Part 2 (13 weeks), and 58 patients in the OLE (52 weeks).
−Removed: At the end of Part 2, 69% (18/26) of rusfertide patients achieved hematocrit control and remained phlebotomy free at 12 weeks, compared to only 19% (5 out of 27) on placebo (p=0.0003).
−Removed: Among the 58 patients that continued into the OLE, as of October 17, 2023 (data cut-off date for the ASH presentation), 57 had been treated for over one year and 37 had been treated for over two years.
−Removed: The median follow-up was 2.1 years and data were provided out to 2.5 years in 21 patients.
−Removed: Results showed that rusfertide, when used in patients previously treated with phlebotomy with or without cytoreductive therapy through two years, resulted in durable hematocrit control, decreased phlebotomy use, long-term tolerability, and no new safety signals in patients with PV.
−Removed: An analysis of the PACIFIC Phase 2 trial was also presented which showed that rusfertide improved markers of iron deficiency in patients with PV.
−Removed: In addition, data was presented regarding the prevalence of thromboembolic events and secondary cancers in PV patients not treated with rusfertide.
−Removed: In February 2024, the full Phase 2 REVIVE trial results, including efficacy and safety data, were published in the NEJM.
−Removed: Updated long-term results from the REVIVE trial presented at the European Hematology Association Congress in June 2024 continued to show a durable positive effect on PV symptomology and other benefits, including iron deficiency as well as an encouraging safety profile.
−Removed: Clinical Efficacy of Rusfertide in REVIVE Trial
−Removed: Data as of October 18, 2024
−Removed: In November 2024, final data from the REVIVE trial was presented at the ASH 2024 Annual Meeting (Figure 3).
−Removed: As of October 18, 2024 (the data cut-off date for presentation at ASH), 50 (71%), 38 (54%), and 17 (24%) patients received rusfertide for ≥2, ≥2.5, or ≥3 years, respectively.
−Removed: Of the 58 patients who entered the REVIVE Part 3 OLE, the median duration of therapy was 131.4 weeks (2.5 years).
−Removed: As of October 18, 2024, 46, or over 80%, of patients have rolled over to the THRIVE trial and are eligible to receive up to two additional years of rusfertide treatment.
−Removed: Trial results showed that rusfertide, when added to therapeutic phlebotomy with or without cytoreductive therapy, achieved long term durable control of hematocrit below the 45% threshold for over three years.
−Removed: Prior to enrollment, the estimated mean phlebotomy rate (“EPHL”) in patients who enrolled in the trial was >5 per year.
−Removed: In Part 1, the EPHL was <1 per year in patients who received rusfertide (N=70).
−Removed: In Part 2 (randomized withdrawal phase), the EPHL was <1 per year and approximately 6.1 per year in the rusfertide and placebo groups, respectively.
−Removed: For patients who continued to Part 3 (Week 42+), the EPHL remained at <1 per year.
−Removed: Patients showed increased mean corpuscular volume and continued improvement and normalization of serum ferritin levels.
−Removed: Platelet levels increased following initiation of rusfertide therapy and stabilized over time and mean leukocyte counts remained stable throughout the trial.
−Removed: The MPN-SAF was used to assess mean change from baseline in the individual symptom score in patients with moderate (score of 4-6 out of 10) or severe (score of 7-10 out of 10) symptoms at baseline.
−Removed: In patients who had moderate or severe symptoms at baseline (score of ≥4 out of 10), there were significant improvements from baseline in fatigue, early satiety, abdominal discomfort, inactivity, problems with concentration, night sweats, and itching at the end of Part 3.
−Removed: Overall, 18 (26%) patients experienced serious adverse events (“SAEs”);
−Removed: most SAEs were unrelated and likely associated with the underlying disease.
−Removed: One patient developed acute myeloid leukemia after treatment discontinuation.
−Removed: After more than 150 patient-years of rusfertide exposure, malignancies were reported in 11 patients (nine patients had skin malignancies);
−Removed: all of these patients had prior risk factors that may have contributed to development of these malignancies.
−Removed: There was no obvious correlation between increased exposure to rusfertide and the malignancies reported.
−Removed: Seven thrombotic events (six arterial and one venous) occurred in six patients who all had high-risk PV.
−Removed: No thrombotic events have been reported in patients with low-risk PV as of October 18, 2024.
−Removed: These results indicate that rusfertide continued to demonstrate a positive clinical impact in the treatment of PV patients.
−Removed: With more than three years of data showing strong and continued improvements in hematocrit as well as encouraging evidence of symptoms improvement, we believe rusfertide continues to show its potential as a first-in-class erythrocytosis-focused treatment option for patients with PV.
−Removed: Rusfertide Phase 3 PV Trial Design
−Removed: We initiated VERIFY, a global double-blind, placebo-controlled Phase 3 clinical trial of rusfertide in PV for approximately 250 patients, in the first quarter of 2022 (Figure 4).
−Removed: We expect to announce top-line data for the trial’s 32-week primary efficacy endpoint in the first quarter of 2025, potentially leading to an NDA filing in the fourth quarter of 2025.
−Removed: We currently have the following designations for rusfertide in PV:
−Removed: ● The FDA granted orphan drug designation for rusfertide for the treatment of PV in June 2020;
−Removed: ● The European Medicines Agency (“EMA”) granted orphan drug designation for rusfertide for the treatment of PV in October 2020;
−Removed: ● The FDA granted fast track designation for rusfertide for the treatment of PV in December 2020.
−Removed: Rodent Carcinogenicity Studies
−Removed: Rat carcinogenicity study.
−Removed: In the fourth quarter of 2024, we received the draft audited pathology report from our two-year study evaluating the carcinogenicity potential of rusfertide when administered once weekly.
−Removed: The draft report concluded that there were no carcinogenicity-related findings associated with rusfertide.
−Removed: We expect to receive the final audited report during the first quarter of 2025 which will then be submitted to the FDA.
−Removed: RasH2 mouse carcinogenicity study .
−Removed: In 2021, we completed a 26-week rasH2 transgenic mouse carcinogenicity study related to rusfertide.
−Removed: In the rasH2 study, there were rusfertide related findings associated with benign squamous cell papilloma and malignant squamous cell carcinoma.
−Removed: Our rusfertide clinical trials were placed on a brief clinical hold from mid-September to early October 2021 following our receipt of the results of the RasH2 mouse study.
+Added: Protagonist Therapeutics, Inc.
+Added: (referred to as “Protagonist,” the “Company,” “we,” “our” or “us”) is an integrated discovery and development company with a validated technology platform.
+Added: Our programs fall into three broad therapeutic areas:
+Added: (i) inflammation and immunology (“I&I”), (ii) hematology and (iii) metabolic diseases.
+Added: Our aim is to develop medicines for biologically and commercially validated targets which demonstrate a strong differentiation compared to existing therapies.
+Added: Our Development Products and Discovery Programs
+Added: Icotyde™ (icotrokinra)
+Added: Icotyde™ (icotrokinra) is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (“IL-23R”), which underpins the inflammatory response in psoriasis and offers potential in other IL-23-mediated diseases.
+Added: Icotyde is licensed to Janssen Biotech, Inc., a Johnson & Johnson company (“JNJ”), under a license and collaboration agreement initially entered into in 2017.
+Added: Following Icotyde’s joint discovery by Protagonist and JNJ scientists, pursuant to the license and collaboration agreement, we were primarily responsible for the development of Icotyde through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond.
+Added: In July 2025 and September 2025, respectively, JNJ submitted a New Drug Application (“NDA”) to the U.S.
+Added: Food and Drug Administration (“FDA”) and an application to the European Medicines Agency (“EMA”) seeking the first approval of Icotyde for the treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe plaque psoriasis.
+Added: JNJ has disclosed that it expects to launch Icotyde in the United States in 2026, subject to regulatory approval.
+Added: Rusfertide is a first-in-class investigational injectable mimetic of the natural hormone hepcidin in development for the treatment of the rare blood disorder polycythemia vera (“PV”).
+Added: We discovered rusfertide, advanced it into Phase 3 development, and in early 2024 entered into a co-development and co-commercialization arrangement with Takeda Pharmaceuticals, Inc.
+Added: (“Takeda”) under a license and collaboration agreement entered into in January 2024.
+Added: remained primarily responsible for clinical development activities through rusfertide’s NDA filing for the treatment of erythrocytosis in patients with PV, which we and Takeda submitted in December 2025.
+Added: Rusfertide has also received Orphan Drug status, Fast Track designation and, in August 2025, Breakthrough Therapy designation (“BTD”).
+Added: BTD is a process designed to expedite the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.
+Added: BTD also provides eligibility for priority NDA review, and Orphan Drug status qualifies sponsors for various incentives, including the potential for extended market exclusivity.
+Added: Takeda has disclosed that it expects to launch rusfertide in the second half of 2026, subject to regulatory approval.
+Added: IL-17 Program
+Added: We are developing PN-881, a potential best-in-class oral peptide IL-17 antagonist, for the treatment of immune-mediated skin diseases.
+Added: PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), and may offer potential treatment options for plaque psoriasis, psoriatic arthritis (“PsA”), h idradenitis suppurativa (“HS”), and spondyloarthritis.
+Added: In October 2025, the first human subject was dosed in our Phase 1 trial of PN-881 (ClinicalTrials.gov identifier NCT07153146) evaluating its safety, tolerability, pharmacokinetics and pharmacodynamics in healthy adults.
+Added: Results of the PN-881 Phase 1 study are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial.
+Added: We expect to complete the Phase 1 study in mid-2026 and initiate a Phase 2 study of PN-881 in psoriasis by the end of 2026.
+Added: Obesity Program
+Added: In June 2025, we nominated PN-477, a potential best-in-class novel triple GLP-1, GIP and GCG receptor agonist peptide with oral (“PN-477o”) and subcutaneous (“PN-477sc”) routes of administration, as a development candidate for the treatment of obesity.
+Added: We designed PN-477 to offer an optimal combination of total body weight loss, improved gastrointestinal tolerability and fat to lean mass ratio, with the dosing convenience of a once-daily oral agent and the added optionality of a once-weekly subcutaneous administration.
+Added: IND-enabling studies of PN-477 are underway and the initiation of Phase 1 clinical studies in PN-477sc and PN-477o are anticipated by mid-2026 and in the second half of 2026, respectively.
+Added: In December 2025, we nominated development candidate PN-458, a potential best-in-class novel dual GLP-1 and GIP receptor agonist peptide, as a development candidate for the treatment of obesity, with optionality for both an oral (“PN-458o”) and subcutaneous (“PN-458sc”) formulation.
+Added: IND-enabling studies for PN-458o and PN-458sc are ongoing.
+Added: Oral Hepcidin Program
+Added: In December 2025, we nominated development candidate PN-8047, an orally administered hepcidin functional mimetic small molecule, which we believe may be complementary to the injectable rusfertide for offering the best treatment options for PV.
+Added: IND-enabling studies for PN-8047 are ongoing.
+Added: Other Programs
+Added: We also have a number of pre-clinical stage drug discovery programs addressing biologically and commercially validated targets, including an oral IL-4R alpha antagonist for the treatment of atopic dermatitis and moderate-to-severe asthma, and amylinR-based oral and subcutaneous mono- and poly-agonists for the treatment of obesity.
+Added: Significant Cash Resources
+Added: We ended fiscal 2025 with cash, cash equivalents and marketable securities of approximately $646.0 million, as compared to cash, cash equivalents and marketable securities of approximately $559.2 million as of December 31, 2024.
+Added: In 2026 and beyond, we are eligible to receive significant milestone, royalty and other payments from our collaborations with JNJ and Takeda, as described below.
+Added: The receipt of future royalties and commercial milestones is contingent upon the relevant products receiving FDA approval and achieving a successful commercial launch.
+Added: Collaboration Agreements
+Added: JNJ License and Collaboration Agreement
+Added: We and JNJ are parties to a license and collaboration agreement related to the development and commercialization of Icotyde.
+Added: We entered into the agreement in July 2017, and amended it in May 2019, July 2021 and November 2024 (as amended, the “JNJ License and Collaboration Agreement”).
+Added: Pursuant to the JNJ License and Collaboration Agreement, we were primarily responsible for the discovery, IND-enabling studies and the initial Phase 1 study for Icotyde, and JNJ is primarily responsible for conducting all further development.
+Added: We have earned a total of $337.5 million in milestone payments from JNJ under the agreement, including a $165.0 million milestone payment earned in the fourth quarter of 2024.
+Added: We are eligible to receive up to $630.0 million in future development and sales milestone payments, including the following potential milestones:
+Added: We will also receive upward tiering royalties on net worldwide Icotyde product sales at percentages ranging from 6% to 10%.
+Added: Our weighted average royalty rate on the first $4.0 billion in annual net sales is 7.25%, and the rate on net sales over $4.0 billion is 10%.
+Added: See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for additional information.
Takeda Collaboration Agreement
−Removed: In January 2024, we entered into a worldwide license and collaboration agreement for the development and commercialization of rusfertide with Takeda.
−Removed: See Part II, Item 7.
−Removed: “Management’s Discussion and Analysis – Overview” and Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
−Removed: OVERVIEW OF DISEASES DRIVEN BY IL-23 AND IL-17 PATHWAYS
−Removed: IL-23 is a member of the Interleukin 12 (“IL-12”) family of cytokines with pro-inflammatory and immune stimulatory properties.
−Removed: Cytokines are cell signaling proteins that are released by cells and affect the behavior of other cells.
−Removed: Binding of the IL-23 ligand to the IL-23R receptor leads to an expression of pro-inflammatory cytokines involved in the local tissue autocrine cascade that is an important pathway of many inflammatory diseases, including psoriasis, PsA and inflammatory bowel disease (“IBD”).
−Removed: The injectable antibody drug Stelara® (marketed for psoriasis, PsA, UC and CD) is a p40 antagonist antibody that inhibits both the IL-23 and IL-12 pathways.
−Removed: Next-generation antibody drugs, such as Tremfya® and Skyrizi®, target the p19 subunit of the IL-23 ligand and are specific inhibitors of the IL-23 pathway, which is believed to be the critical driver of local tissue pathology.
−Removed: Tremfya® is approved in psoriasis, PsA and UC and has completed successful Phase 3 clinical trials in CD.
−Removed: Skyrizi® is approved in psoriasis, PsA, UC and CD.
−Removed: The anti-IL-23 antibody Omvoh® (mirikizumab) has been approved in UC and CD, and the anti-IL-23 antibody Ilumya® trial (tildrakizumab) has been approved in psoriasis.
−Removed: IL-23 is a pro-inflammatory cytokine with immune stimulatory properties.
−Removed: Binding of the IL-17 ligand to the IL-17R receptor leads to an expression of pro-inflammatory cytokines involved in the local tissue autocrine cascade that is an important pathway of many inflammatory diseases, including psoriasis, PsA, spondyloarthropathies, and HS).
−Removed: The injectable antibody drugs Cosentyx® and Taltz® (marketed for psoriasis, PsA, ankylosing spondylitis (“AS”) and non-radiographic axial spondyloarthropathies (“nr-axSpA”), with Cosentyx® also marketed for HS, and pediatric enthesitis-related arthritis) are IL-17A antagonist antibodies that inhibit the IL-17 pathway.
−Removed: The injectable antibody drug Bimzelx® blocks both IL-17A and IL-17F, thereby more completely blocking the IL-17 pathway by blocking its three dimeric forms – IL-17AA, -AF, and -FF.
−Removed: Bimzelx® is approved in psoriasis, PsA, AS, nr-axSpA, and HS.
−Removed: The injectable antibody Saliq® is an antibody that blocks the IL-17 receptor A, thereby blocking the IL-17 pathway, and is approved in psoriasis.
−Removed: Psoriasis is a chronic inflammatory disease of the skin that affects 130 million people worldwide and over 8 million in the United States, translating to 2-3% of the adult population.
−Removed: Psoriasis is associated with several comorbid conditions including cardiovascular disease and obesity, and 30% of psoriasis patients develop arthritic complications.
−Removed: Psoriasis is also associated with significantly decreased quality of life for patients.
−Removed: Plaque p soriasis is the most common form of psoriasis, which is recognized as the most prevalent immune-mediated inflammatory disease, involving skin and joints and associated with abnormalities of other systems.
−Removed: Several factors, such as surface area covered and symptom burden, impact whether one’s psoriasis is considered mild, moderate, or severe.
−Removed: Typically, 3-10% of affected body surface area is considered moderate psoriasis, and more than 10% is considered severe psoriasis.
−Removed: Global market sales for psoriasis therapies in 2023 were $24.9 billion, with U.S.
−Removed: market sales of $18.4 billion.
−Removed: The global market forecast for 2033 anticipates sales of $32.0 billion, with U.S.
−Removed: market sales of $23.8 billion.
−Removed: Identification of the IL-23/IL-17 axis as the key pathway driving psoriatic inflammation has led to the development of more effective and safer systemic therapies that inhibit IL-17 (e.g., Taltz®, Cosentyx®, Bimzelx®, Saliq®) and IL-23 (e.g., Tremfya®, Skyrizi®, Ilumya®).
−Removed: These biologics have revolutionized the treatment of moderate-to-severe psoriasis, with superior efficacy and safety compared to conventional oral therapies (e.g., methotrexate, cyclosporin), and first-generation biologics (e.g., anti-TNFs, Stelara®).
−Removed: The anti-IL-17 class is ineffective in IBD, surprisingly showing overall worsening of disease in Phase 2 trials, which is reflected in the product labels.
−Removed: There is still an unmet need for new therapies.
−Removed: Only 25% of biologic eligible moderate-to-severe psoriasis patients are treated with a biologic.
−Removed: The parenteral route of administration for these advanced biologics poses a patient level barrier to entry.
−Removed: oral medicines have been approved in moderate-to-severe psoriasis.
−Removed: Otezla® was approved in 2014.
−Removed: It is the least effective of all drugs approved since 2004 but is used widely because of a perceived positive safety profile.
−Removed: In 2022, the first TYK2 inhibitor, Sotyktu®, was approved.
−Removed: A second TYK2 inhibitor, TAK-279 is in Phase 3 trials for moderate-to-severe plaque psoriasis.
−Removed: We believe there is still significant need for safe and effective oral therapies in moderate-to-severe psoriasis.
+Added: In January 2024, we entered into a worldwide license and collaboration agreement for rusfertide with Takeda (the “Takeda Collaboration Agreement”) related to rusfertide (and specified second-generation injectable hepcidin mimetic compounds developed and commercialized under the agreement that are not currently in development).
+Added: In December 2025, Takeda submitted an NDA to the FDA for rusfertide in PV.
+Added: We were primarily responsible for the clinical development of rusfertide through NDA filing and remain primarily responsible for the conduct of ongoing rusfertide long-term extension studies.
+Added: Under the terms of the agreement, we received an upfront payment of $300.0 million in April 2024 and a $25.0 million milestone payment in September 2025 upon completion of the Phase 3 VERIFY clinical trial (NCT05210790) report.
+Added: Under the Takeda Collaboration Agreement, we and Takeda share equally in profits and losses (50% to us and 50% to Takeda) associated with rusfertide in the United States.
+Added: We also will receive tiered royalties ranging from 10% to 17% on ex-U.S.
+Added: net sales of rusfertide.
+Added: However, we have the right under the Takeda Collaboration Agreement to opt-out of the U.S.
+Added: profit and loss sharing arrangement.
+Added: We currently expect to exercise that right in the second quarter of 2026, within the 90-day opt-out window beginning 120 days after the NDA filing date as prescribed in the agreement.
+Added: If we exercise our opt-out right, Takeda will have an exclusive worldwide license to develop and commercialize rusfertide, and we will receive royalties of 14% to 29% on annual worldwide net sales, with a weighted average royalty rate of 21% at $1.5 billion in net sales and a rate of 29% for net sales over $1.5 billion.
+Added: In addition, under the agreement, we are eligible to receive up to an aggregate of $975.0 million in development, regulatory and sales milestones, including the $25.0 million milestone payment already received in September 2025, and up to $400.0 million in payments for exercising the opt-out right.
+Added: Upcoming potential development milestones and potential sales milestones under the agreement if we exercise our opt-out right include the following:
+Added: If we do not exercise our opt-out right, we will be eligible to receive up to an aggregate of $305.0 million in development, regulatory and sales milestones and will continue sharing equally in profits and losses associated with rusfertide in the United States.
+Added: In addition, we will receive tiered royalties ranging from 10% to 17% on ex-U.S.
+Added: net sales of rusfertide.
+Added: See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for further details related to the agreement, including our opt-out rights.
+Added: OUR INFLAMMATORY AND IMMUNOLOGY (“I&I”) PROGRAM
+Added: Our I&I program focuses on immune-mediated inflammatory diseases driven by the IL-23 and IL-17 pathways.
+Added: The program includes Icotyde, an IL-23R peptide antagonist licensed to JNJ, and PN-881, a wholly owned oral IL-17 antagonist.
+Added: Both candidates leverage our proprietary peptide platform to develop targeted, orally delivered therapies for multiple chronic inflammatory diseases.
+Added: Disease Background and Market Opportunity
+Added: The IL-23 and IL-17 signaling pathways are central drivers of multiple immune-mediated inflammatory diseases, including psoriasis, PsA, HS, axial spondyloarthritis (“axSpA”), and inflammatory bowel disease (“IBD”).
+Added: These chronic conditions are associated with significant morbidity, impaired quality of life, and long-term healthcare utilization.
+Added: Psoriasis is a chronic inflammatory skin disease affecting approximately 130 million people worldwide and over 8 million people in the United States, or 2% to 3% of the adult population.
+Added: Comorbidities include cardiovascular disease and obesity, and up to 30% of patients develop arthritic complications.
+Added: Plaque psoriasis is the most common form, with severity classified by affected body surface area:
+Added: moderate (3% to 10%) and severe (>10%).
+Added: Global sales for psoriasis therapies were $25.4 billion in 2024 and are expected to exceed $39.0 billion by 2030.
+Added: Targeting the IL-23/IL-17 axis has led to more effective systemic therapies.
+Added: Key IL-23 inhibitors include Stelara® (p40 antagonist;
+Added: psoriasis, PsA, UC, CD), Tremfya®, Skyrizi® (p19-specific;
+Added: psoriasis, PsA, UC, CD), Omvoh® (mirikizumab;
+Added: UC, CD), and Ilumya® (tildrakizumab;
+Added: IL-17 inhibitors include Cosentyx®, Taltz®, Bimzelx® (blocks IL-17A and IL-17F), and Siliq® (IL-17 receptor A).
+Added: The anti-IL-17 class is ineffective in IBD.
+Added: Only 25% of biologic-eligible moderate-to-severe psoriasis patients are treated with biologics, in part due to the parenteral route.
+Added: This treatment gap highlights the impact of chronic injectable administration, patient preference, and access considerations, and underscores the need for effective oral therapies that can expand treatment adoption without compromising efficacy.
+Added: Oral therapies, such as Otezla® (2014, PDE4 inhibitor) and Sotyktu® (2022, TYK2 inhibitor), offer alternatives, with second-generation TYK2 inhibitors in late-stage development.
+Added: Despite the clinical success of injectable biologics targeting the IL-23 and IL-17 pathways, their parenteral administration and long-term treatment burden continue to limit utilization, supporting demand for oral therapies that can deliver comparable efficacy with improved convenience.
Psoriatic Arthritis
2 unchanged sentences
Many patients with active PsA may have mild psoriasis and many patients with severe psoriasis may have only mild PsA symptoms.
−Removed: PsA is associated with several chronic conditions.
−Removed: PsA may present even before skin symptoms in 10% to 15% of patients.
−Removed: Cardiovascular comorbidities have a higher prevalence in PsA than psoriasis and can impact lifespan and quality of life.
−Removed: Several new targeted therapies have been approved for use in PsA, with additional therapies in development.
−Removed: These advances have improved outcomes, including reductions in musculoskeletal symptoms, skin manifestations and radiographic joint damage.
−Removed: Many of the same drugs approved in psoriasis are also approved in PsA.
−Removed: One notable exception is that the JAK inhibitors, Xeljanz® and Rinvoq®, are approved in PsA without the respective label in psoriasis.
+Added: PsA is associated with several chronic conditions and may present even before skin symptoms in 10% to 15% of patients.
+Added: Cardiovascular comorbidities have a higher prevalence in PsA than psoriasis and can impact both lifespan and quality of life.
+Added: Global market sales of PsA therapies were approximately $7.1 billion in 2024 and are expected to reach more than $10.0 billion in 2034.
+Added: Treatment options typically overlap with psoriasis therapies;
+Added: exceptions to this include JAK inhibitors (Xeljanz® and Rinvoq®), which are approved for PsA but not psoriasis.
+Added: As a result, therapies that are effective across both skin and joint manifestations and that offer improved convenience may provide meaningful clinical and patient-reported benefits in PsA.
Hidradenitis Suppurativa
−Removed: HS is a chronic, debilitating, inflammatory follicular skin disease with recurring painful flare-ups that affected approximately 2.9 million people in the U.S.
−Removed: and 6.3 million worldwide in 2024.
−Removed: HS can progress and worsen over time, with tunnels forming under the skin between abscesses, which can lead to scarring.
−Removed: HS symptoms typically affect intertriginous areas of the skin, such as the breasts, buttocks, groin, inner thighs, and under the arms.
−Removed: The suppuration is often accompanied by a foul smell, and the psychosocial burden, including isolation, can be severe.
−Removed: HS is associated with frequent, long-term sick leave, often having a substantial socio-economic impact.
−Removed: Global market sales for HS therapies in 2024 were $1.5 billion, with U.S.
−Removed: market sales of $1.2 billion.
−Removed: The global market forecast for 2034 anticipates sales of $6.5 billion, with U.S.
−Removed: market sales of $5.4 billion.
−Removed: Treatment for HS depends on the severity of the disease and traditionally included skin care, topical medications, antibiotics, acitretin, hormonal medications, and, in severe cases, surgical removal of the affected skin.
−Removed: Several new targeted therapies have more recently been approved, including an injectable antibody drug Humira®, which binds to tumor necrosis factor alpha (“TNFα”), as well as the anti-IL-17 drugs Cosentyx® and Bimzelx®.
−Removed: Though these advances have improved outcomes, there remains significant unmet need for new therapies.
+Added: HS affects approximately 2.9 million patients in the United States and 6.3 million patients globally.
+Added: It is a chronic, painful inflammatory skin disease that significantly impacts quality of life and productivity.
+Added: Global HS therapy sales were approximately $1.5 billion in 2024, with global sales projected to reach $6.5 billion ($5.4 billion in the United States) by 2034.
+Added: Targeted therapies include Humira®, Cosentyx®, and Bimzelx®.
+Added: While recent biologic approvals have improved outcomes for some patients, HS remains an area of high unmet need, particularly for therapies that combine high efficacy with the convenience of oral administration for long-term disease management.
Axial Spondyloarthritis
−Removed: Axial spondyloarthritis (“axSpA”) is a systemic disease leading to arthritis affecting the spine and the sacroiliac joint that affected approximately 2.9 million people in the U.S.
−Removed: and 4.7 million patients worldwide in 2024.
−Removed: AxSpA has a strong genetic predisposition most commonly associated with HLA-B27.
−Removed: Over time, the disease may progress from nr-axSpA, which is associated with damage that may not be visible in X-rays but may be seen on magnetic resonance images, to AS, also known as radiographic axSpA, with damage to the sacroiliac joints and spine visible on X-rays.
−Removed: Severe disease can lead to fusion of the vertebrae, a condition referred to as bamboo spine.
−Removed: Men are more likely to accrue radiographic joint damage, whereas women tend to experience comparatively worse quality of life and disease activity.
−Removed: The disease can occur at any age but typically begins between ages 20 and 40.
−Removed: AS is more common in men than in women.
−Removed: However, nr-axSpA may be just as common in women as in men.
−Removed: It is less common among African Americans than people of other racial backgrounds.
−Removed: Global market sales for axSpA therapies in 2024 were $7.5 million, with U.S.
−Removed: market sales of $6.0 million.
−Removed: The global market forecast for 2034 anticipates sales of $10.7 million, with U.S.
−Removed: market sales of $8.7 million.
−Removed: Therapeutic options for patients with axSpA have expanded significantly over the past two decades.
−Removed: Patients who have failed non-steroidal anti-inflammatory drugs have multiple therapeutic options, including TNFα inhibitors (Enbrel®, Humira®, Remicade®, Simponi®, Cimzia®), IL-17 (Cosentyx®, Taltz®, Bimzelx®) and JAK inhibitors (Xeljanz®, Rinvoq®).
−Removed: Inflammatory Bowel Disease (“IBD”)
−Removed: IBD is a group of chronic autoimmune and inflammatory conditions of the colon and small intestine, consisting primarily of UC and CD.
−Removed: In UC, inflammation may be limited to part of the colon or extend through its entirety.
−Removed: UC is primarily characterized by ulceration of the intestinal surface, accompanied by rectal bleeding and frequent, urgent bowel movements.
−Removed: CD occurs anywhere along the GI tract, commonly affecting the small intestine and the proximal large intestine.
−Removed: CD complications may include strictures and fistula, which penetrate all layers of the intestine.
−Removed: UC is usually diagnosed earlier than CD due to bleeding symptoms.
−Removed: Patients with CD may initially present with abdominal pain, fatigue and anorexia, which can be misdiagnosed.
−Removed: Both diseases’ peak diagnosis years are in young adulthood and are found about equally in both males and females.
−Removed: Management is lifelong and affects school attendance, graduation rates, childbearing and work productivity.
−Removed: IBD prevalence is increasing worldwide and is correlated with the adoption of western diets and lifestyle, as well as genetic factors (5-20% of affected patients have a first degree relative with the disease).
−Removed: According to the Crohn’s & Colitis Foundation, IBD is diagnosed in over 0.7% of Americans, resulting in a population of approximately 2.4 million patients in the United States.
−Removed: In 2023, global sales for UC therapies were approximately $7.8 billion, and the market is expected to grow to $13.2 billion by 2030.
−Removed: In 2023, global sales for CD therapies were estimated to be $15.2 billion, with anticipated growth to $18.1 billion by 2030.
−Removed: For many years, tumor necrosis factor-alpha (“TNF-α”) antibody drugs were the primary treatment for moderate-to-severe IBD.
−Removed: Humira® and Remicade® are injectable and infused, respectively.
−Removed: Approximately one third of IBD patients do not respond to TNF-α antibody drugs and approximately another 30% to 40% become refractory within the first year of treatment.
−Removed: Additionally, TNF-α antibody drugs may predispose patients to an increased risk of serious infection and the development of anti-drug antibodies, which over time can cause loss of drug response.
−Removed: More recently, antibody products focused on potentially safer mechanisms of action have been gaining market share.
−Removed: One such product is Takeda’s Entyvio®, which targets the α4β7 integrin pathway.
−Removed: Takeda reported 2023 sales of Entyvio® of approximately $5.2 billion.
−Removed: Similarly, Johnson & Johnson’s Stelara®, which targets the IL-12 and IL-23 pathways, has gained significant traction.
−Removed: Johnson & Johnson global sales of Stelara® (approved for psoriasis, PsA, moderate-to-severe CD and UC) were $10.4 billion in 2024.
−Removed: Three anti-IL-23 mAbs have been evaluated in IBD.
−Removed: Skyrizi® and Omvoh® are approved in UC and CD, and Tremfya® is approved in UC and recently completed successful Phase 3 clinical trials in CD.
−Removed: The pan-JAK inhibitor Xeljanz® is approved in UC and the more selective JAK1/3 inhibitor Rinvoq® was approved in 2022 for UC and CD.
−Removed: The S1P1 modulator class of oral small molecules has also demonstrated efficacy in IBD, with Zeposia® approved in UC (but not CD) in 2021, and etrasimod approved in UC in 2023.
−Removed: The S1P1 class is associated with immunosuppression, cardiac, pulmonary and ocular toxicities.
−Removed: The development of new, potent and targeted orally delivered therapies for IBD may offer safer and more effective treatment options, alone or in combination, for moderate-to-severe IBD patients.
−Removed: In addition, many clinicians continue to advocate for earlier introduction of targeted therapeutics in mild-to-moderate IBD to prevent disease progression and irreversible gastrointestinal damage.
−Removed: Given that the most effective agents in IBD induce remission in no more than 30% of patients, there has been much recent interest in combination therapies to break through this “therapeutic ceiling.” In 2022, JNJ reported results of the VEGA study, the first randomized double bind clinical trial to assess the combination of an anti-TNF (Simponi®) with an anti-IL-23 (Tremfya®) in moderate-to-severe UC.
−Removed: In the Phase 2a POC trial, investigators found 83.1% of patients in the treatment group achieved a clinical response and 36.6% of patients treated with the combination therapy achieved clinical remission.
−Removed: The high rates of clinical response and remission are both higher than the response and remission rates of patients treated with guselkumab alone (74.6%;
−Removed: 21.1%) and golimumab alone (61.1%;
−Removed: Hence, we believe the IL-23 inhibition mechanism is a potentially paradigm shifting combination strategy to improve remission rates in UC.
+Added: axSpA affects approximately 2.0 million U.S.
+Added: patients and 3.8 million patients globally.
+Added: It is a systemic arthritis affecting the spine and sacroiliac joints, with progression from non-radiographic (nr-axSpA) to radiographic disease (AS).
+Added: Global axSpA therapy sales were $4.7 billion in 2024, with global sales projected to reach $7.2 billion ($5.9 billion in the United States) by 2034.
+Added: Treatments include TNFα inhibitors, IL-17 inhibitors, and JAK inhibitors.
+Added: Despite the availability of multiple biologic and targeted therapies, many patients experience incomplete symptom control or treatment fatigue, highlighting the need for additional therapeutic options that reduce long-term burden.
+Added: Inflammatory Bowel Disease
+Added: IBD, comprising ulcerative colitis (“UC”) and Crohn’s disease (“CD”) is diagnosed in over 0.7% of Americans, resulting in a population of approximately 2.4 million patients in the United States .
+Added: UC primarily involves colon inflammation and bleeding, while CD affects any gastrointestinal tract segment and may cause strictures and fistulae.
+Added: Management is lifelong and impacts quality of life and productivity.
+Added: Global 2023 sales for UC therapies were $7.8 billion, with global sales projected to reach $18.8 billion by 2030.
+Added: Global 2023 sales for CD therapies were $15.2 billion, with global sales projected to reach $18.7 billion by 2030.
+Added: Treatment options for UC and CD include TNF-α inhibitors, α4β7 integrin antagonists (Entyvio®), IL-23 inhibitors (Stelara®, Tremfya®, Skyrizi®, Omvoh®), JAK inhibitors, and S1P1 modulators.
+Added: Despite this expanding therapeutic landscape, remission rates remain limited and loss of response over time is common, underscoring the need for more effective and better-tolerated oral therapies, including those suitable for combination use.
+Added: Current Therapeutic Landscape and Unmet Medical Needs
+Added: Treatment paradigms across IL-23- and IL-17-mediated diseases are dominated by injectable biologic therapies, including antibodies targeting IL-23, IL-17, TNF-α, and related pathways.
+Added: These biologics have demonstrated efficacy and are widely used in moderate-to-severe disease across multiple indications.
+Added: Despite these advances, unmet medical needs remain.
+Added: A substantial proportion of biologic-eligible patients remain untreated, in part due to the burden of chronic injections, tolerability considerations, and access limitations.
+Added: Safety considerations associated with systemic immunosuppression further constrain long-term treatment options.
+Added: Orally delivered, targeted therapies may reduce burden, improve adherence, and expand patient access.
+Added: Our Development Candidates
An Oral IL-23 Receptor Antagonist
−Removed: JNJ License and Collaboration Agreement
+Added: Icotyde, an orally delivered IL-23R specific antagonist for the potential treatment of psoriasis, PsA and IBD indications, was discovered through our proprietary technology platform.
+Added: IL-23, a member of the IL-12 family of pro-inflammatory cytokines, is a protein that regulates inflammatory and immune function and plays a key role in the development of IBD.
We have a worldwide license and collaboration agreement with JNJ to research, develop and co-detail IL-23R antagonist compounds for all indications, including IBD.
−Removed: See Part II, Item 7.
−Removed: “Management’s Discussion and Analysis –
−Removed: Overview” and Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
+Added: Pursuant to the JNJ License and Collaboration Agreement, we were responsible for the discovery, IND-enabling studies, and the initial Phase 1 study for Icotyde, and JNJ is responsible for conducting all further development.
+Added: See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
JNJ is an experienced innovator in therapeutics targeting the IL-23 pathway.
−Removed: Stelara® is a monoclonal antibody targeting IL-12 and IL-23 through their common p40 subunit is approved in psoriasis, PsA, CD and UC.
−Removed: Stelara® generated $10.4 billion in sales in 2024.
−Removed: Tremfya® is a specific IL-23 monoclonal antibody.
−Removed: It is approved in psoriasis and PsA and has completed successful Phase 3 trials in UC and CD.
−Removed: Tremfya® generated $3.7 billion in sales in 2024.
−Removed: We believe that in both psoriasis and IBD, there is an urgent need for safe and effective oral therapies.
−Removed: It is notable that Stelara® lost patent exclusivity in 2023 with biosimilar competition expected.
−Removed: Icotrokinra, an orally delivered IL-23R specific antagonist for the potential treatment of psoriasis, PsA and IBD indications, was discovered through our peptide technology platform.
−Removed: IL-23, a member of the IL-12 family of pro-inflammatory cytokines, is a protein that regulates inflammatory and immune function and plays a key role in the development of IBD.
−Removed: By blocking IL-23R, we believe icotrokinra may improve disease symptoms while potentially minimizing the risk of systemic side effects.
−Removed: During the fourth quarter of 2021, a decision was made by JNJ to advance development of icotrokinra.
−Removed: For icotrokinra, JNJ is primarily responsible for the conduct of all further development, and we were primarily responsible for the discovery, IND-enabling studies and the initial Phase 1 study.
−Removed: Clinical Development of Icotrokinra
−Removed: In February 2022, JNJ initiated FRONTIER 1, a 255-patient Phase 2b clinical trial of icotrokinra in moderate-to-severe plaque psoriasis, which was completed in December 2022.
−Removed: FRONTIER 1 was a randomized, multicenter, double-blind, placebo-controlled trial that evaluated three once-daily dosages and two twice-daily dosages of icotrokinra taken orally.
−Removed: The primary endpoint of the trial was the proportion of patients achieving PASI-75 at 16 weeks.
−Removed: In July 2023, we announced updated positive topline results from the trial, which were presented by JNJ at the World Congress of Dermatology in Singapore.
−Removed: Icotrokinra achieved the trial’s primary and secondary efficacy endpoints.
−Removed: A statistically significant greater proportion of patients who received icotrokinra achieved PASI-75 responses as well as PASI-90 and PASI-100 responses compared to placebo at week 16 in all five of the trial’s treatment groups.
−Removed: A clear dose response was observed across an eight-fold dose range.
−Removed: Treatment was well tolerated, with no meaningful difference in frequency of adverse events across treatment groups versus placebo.
−Removed: At JNJ’s Enterprise Business Review in December 2023, JNJ highlighted icotrokinra as a potential first- and best-in-class targeted oral IL-23 peptide antagonist with potential across multiple indications, including plaque psoriasis, PsA and inflammatory bowel disease, with potential peak year sales projected at greater than $5.0 billion.
−Removed: JNJ IL-23 monoclonal antibody drugs Stelara and Tremfya generated approximately $14.1 billion in revenues in 2024.
−Removed: In February 2024, the icotrokinra Phase 2b FRONTIER 1 trial results in adults living with moderate-to-severe plaque psoriasis were published in the NEJM.
−Removed: In March 2024, data presented at the American Academy of Dermatology 2024 Annual Meeting showed that, in the Phase 2b FRONTIER 2 trial, icotrokinra maintained high rates of skin clearance through 52 weeks in adults with moderate-to-severe plaque psoriasis.
−Removed: In August 2024, positive pre-clinical and clinical pharmacokinetic, pharmacodynamic and safety data for icotrokinra was published in the journal, Scientific Reports.
−Removed: Three Company-sponsored poster presentations and one Company-sponsored oral presentation were delivered at the 2024 European Academy of Dermatology and Venereology Congress in September 2024.
−Removed: JNJ initiated six additional icotrokinra trials in psoriasis and one in UC, as discussed above.
−Removed: All of the trials in the ICONIC program use the 200 mg q.d.
−Removed: immediate release formulation of icotrokinra from the FRONTIER 1 trial.
−Removed: In November 2024, we announced positive topline results from ICONIC-LEAD and ICONIC-TOTAL Phase 3 trials of icotrokinra in individuals 12 years of age and older with moderate to severe plaque psoriasis.
−Removed: In the ICONIC-LEAD trial, once-daily icotrokinra showed significant skin clearance versus placebo in adults and adolescents with moderate to severe plaque psoriasis.
−Removed: At week 16, nearly two-thirds (64.7%) of patients treated with icotrokinra achieved IGA scores of 0/1, and 49.6% achieved PASI 90, compared to 8.3% and 4.4% on placebo, respectively.
−Removed: Further increases in response rates continued to be observed at week 24, with 74.1% of patients treated with icotrokinra achieving IGA scores of 0/1, and 64.9% achieving PASI 90.
−Removed: Safety data was found to be consistent with the Phase 2 FRONTIER 1 and 2 trials.
−Removed: A similar proportion of patients experienced adverse events between icotrokinra and placebo, with 49.3% and
−Removed: 49.1% of participants experiencing a TEAE at week 16.
−Removed: In addition, positive topline results from the Phase 3 ICONIC-TOTAL trial showed once-daily icotrokinra met the primary endpoint of IGA of 0/1 at week 16 compared to placebo.
−Removed: We believe these positive Phase 3 results confirm the efficacy and safety trends that were observed with the previous Phase 2 FRONTIER 1 and 2 studies, highlighting icotrokinra’s potential as a best-in-class oral agent providing a combination of significant skin clearance with demonstrated tolerability in a once-daily pill for treating plaque psoriasis.
−Removed: We believe these results also continue to validate our innovative peptide technology platform and its effectiveness in creating highly differentiated new chemical entities to address unmet needs in various disease areas.
−Removed: Comprehensive results from both ICONIC-LEAD and ICONIC-TOTAL are being prepared for presentation at upcoming medical congresses and we expect these to be shared with health authorities in planned submissions.
+Added: Stelara®, a monoclonal antibody targeting IL-12 and IL-23 through their common p40 subunit, is approved in psoriasis, PsA, CD and UC.
+Added: Stelara® generated $10.4 billion in global sales in 2024 and $6.1 billion in global sales in 2025.
+Added: It is notable that Stelara® lost patent exclusivity in 2023, with expected biosimilar competition.
+Added: Tremfya®, a specific IL-23 monoclonal antibody, is approved in psoriasis, PsA, UC and CD.
+Added: Tremfya® generated $3.7 billion in sales in 2024 and $5.2 billion in 2025.
+Added: At JNJ’s Enterprise Business Review in December 2023, JNJ highlighted Icotyde as a potential first- and best-in-class drug with potential across multiple indications, including plaque psoriasis, PsA and inflammatory bowel disease, with potential peak year sales projected at greater than $5.0 billion.
An Oral IL-17 Receptor Antagonist
−Removed: In the fourth quarter of 2024, we announced the selection of PN-881, a potential best-in-class oral peptide IL-17 antagonist, as a development candidate for the treatment of immune-mediated skin diseases.
−Removed: PN-881 has been evaluated in extensive preclinical studies, including oral stability, potency, tissue distribution, and pharmacokinetics measurements, and evaluation in immunologic pharmacodynamics and preclinical efficacy models.
−Removed: PN-881 Potently Inhibits IL-17A and IL-17F
−Removed: PN-881 has demonstrated in vitro blockade of IL-17 AA homodimer, FF homodimer and AF heterodimer.
−Removed: In assays using the HT-1080 human fibrosarcoma cell line stimulated with a combination of IL-17 and TNF-a produce IL-6, blocking IL-17 was shown to inhibit IL-6 production.
−Removed: In this assay, PN-881 inhibited 50% of IL-6 production (the IC50) at a concentration of 120 picomoles (“pM”) and showed an IC 90, or 90% inhibition, at 560 pM.
−Removed: This potency was approximately 100-fold greater than the potency of secukinumab, and similar potency to the most potent approved antibody drugs and nanobody therapeutics in development (Figure 5).
+Added: PN-881, a wholly owned oral peptide antagonist of the IL-17 pathway, was selected in the fourth quarter of 2024 as a potential best-in-class oral therapy for the treatment of immune-mediated skin diseases.
+Added: PN-881 was evaluated in extensive preclinical studies, including for oral stability, potency, tissue distribution, and pharmacokinetics measurements, and was evaluated in immunologic pharmacodynamics and preclinical efficacy models.
In multiple preclinical studies with oral dosing, PN-881 showed effective blockade in vivo of IL-17 in serum and skin and achieved pre-clinical proof-of-concept in a skin inflammation rodent disease model.
−Removed: IND-enabling, or foreign equivalent, studies of PN-881 are ongoing or planned, including 7-day and 3-month toxicology studies.
−Removed: Planned clinical studies include a Phase 1 single ascending dose (“SAD”) and multiple ascending dose (“MAD”) study expected to begin in the fourth quarter of 2025.
−Removed: Results of the Phase 1 trial are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial.
−Removed: Rapid expansion into other IL-17 mediated diseases, including PsA, HS and axSpA, is expected to be based on results observed in psoriasis studies.
+Added: We initiated a Phase 1 PN-881 first-in-human study in the fourth quarter of 2025.
+Added: Results of the Phase 1 single ascending dose (“SAD”) and multiple ascending dose (“MAD”) study are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial.
+Added: Rapid expansion into other IL-17 mediated diseases, including PsA, HS and axSpA, is expected to be based on results observed in the psoriasis studies.
We believe an IL-17 antagonist peptide like PN-881, with best-in-class potential as an oral targeted therapy, may offer an attractive therapeutic option for patients with broad opportunity for multiple indications in addition to psoriasis.
−Removed: We expect to initiate a PN-881 first-in-human Phase 1 study in fourth quarter of 2025.
−Removed: PN-943 is a wholly owned investigational orally delivered gut-restricted alpha 4 beta 7 specific integrin antagonist for IBD.
−Removed: We completed a Phase 2 trial of PN-943 in patients with moderate-to-severe UC in early 2023.
−Removed: We do not intend to dedicate further internal resources to clinical development or contract manufacturing activities for our PN-943 clinical program.
−Removed: OUR PEPTIDE TECHNOLOGY PLATFORM
+Added: OUR HEMATOLOGY PROGRAM
+Added: Our hematology and blood disorders program focuses on disorders of iron homeostasis and red blood cell production.
+Added: The program includes rusfertide, an injectable hepcidin mimetic in development for the treatment of PV, partnered with Takeda, and PN-8047, a wholly-owned oral hepcidin functional mimetic.
+Added: Disease Background and Market Opportunity
+Added: PV is a rare myeloproliferative neoplasm commonly associated with a Janus Kinase (“JAK”) 2 mutation.
+Added: It is characterized by overproduction of red blood cells (“RBCs”), which increases the risk of cardiovascular and thrombotic events such as heart attack and stroke, and carries a risk of progression to myelofibrosis or leukemia.
+Added: According to National Comprehensive Cancer Network (“NCCN”) guidelines, risk classification is based on age and history of thrombosis.
+Added: Regardless of risk, NCCN guidelines emphasize maintaining hematocrit below 45% to reduce thrombotic risk.
+Added: There are approximately 155,000 patients diagnosed with PV in the United States, of whom approximately 78,000 are treated, with a similar number of diagnosed patients in Europe.
+Added: Patients are typically diagnosed between ages 50 and 70, with median survival of approximately 14 years.
+Added: Current Therapeutic Landscape and Unmet Medical Needs
+Added: Early-stage PV is often managed with low-dose aspirin and therapeutic phlebotomy, with hydroxyurea used alone or in combination.
+Added: Later-stage patients may receive interferons, such as Besremi® or Pegasys®, or the JAK inhibitor ruxolitinib (Jakafi®).
+Added: These cytoreductive therapies impact multiple cell lines and can be associated with challenging side-effect profiles.
+Added: Despite available treatments, significant unmet medical needs persist:
+Added: ● Inadequate Hematocrit Control :
+Added: Approximately 78% of treated PV patients do not maintain hematocrit below 45%, highlighting persistent thrombotic risk.
+Added: ● Treatment Burden and Tolerability :
+Added: Approximately 55% of treated patients require frequent phlebotomy and high-dose hydroxyurea, creating considerable treatment burden.
+Added: Approximately 16% of patients experience thrombotic events despite treatment.
+Added: ● Safety Concerns :
+Added: Retrospective data presented at the 2023 American Society of Hematology Annual Meeting indicate that PV patients treated with hydroxyurea had nearly double the incidence of cancers compared to phlebotomy-only patients.
+Added: The mechanisms behind this increased risk are not fully understood.
+Added: ● Iron Deficiency :
+Added: Chronic phlebotomy and high RBC turnover exacerbate iron deficiency, underscoring the need for therapies that maintain hematocrit without broad cytoreduction.
+Added: Our Development Candidates
+Added: An Injectable Hepcidin Mimetic
+Added: Rusfertide was discovered through our proprietary technology platform.
+Added: Acting as a hepcidin mimetic, it redistributes iron away from the bone marrow, limiting excess RBC production while maintaining iron availability for other physiological functions.
+Added: Data from the Phase 2 REVIVE trial (NCT04057040) and pivotal Phase 3 VERIFY trial suggest that rusfertide provides persistent hematocrit control, reduces the need for phlebotomy, and does not induce iron deficiency.
+Added: Patients with prior thromboembolic adverse events (“TEAEs”), who are at highest risk, generally did not experience recurrent TEAEs while on rusfertide.
+Added: In January 2024, we entered into a worldwide license and collaboration agreement for the development and commercialization of rusfertide with Takeda.
+Added: See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
+Added: An Oral Hepciden Functional Mimetic
+Added: Our development candidate PN-8047 is an orally administered hepcidin functional mimetic small molecule designed to complement injectable rusfertide and provide additional treatment options for PV.
+Added: PN-8047 has completed extensive preclinical evaluation, including studies of potency, metabolic stability in liver microsomes, oral permeability, pharmacokinetics, and pharmacodynamics.
+Added: PN-8047 has potency similar to rusfertide and greater potency than native hepcidin.
+Added: In preclinical in vivo studies, PN-8047 demonstrated oral bioavailability and a half-life in rodents, cynomolgus monkeys, and dogs sufficient for once-daily dosing.
+Added: PN-8047 also produced sustained serum iron reduction in pharmacokinetic/pharmacodynamic models and demonstrated efficacy in an erythropoietin-induced mouse model of erythropoiesis, including reductions in hemoglobin and hematocrit observed after repeated dosing in cynomolgus monkeys.
+Added: IND-enabling studies for PN-8047 are ongoing.
+Added: Strategic Rationale
+Added: We are advancing rusfertide and PN-8047 to address persistent gaps in the PV treatment landscape through non-cytoreductive modulation of iron homeostasis:
+Added: ● Targeted Mechanism :
+Added: Unlike cytoreductive therapies, both candidates specifically regulate RBC production via iron redistribution, potentially offering improved tolerability.
+Added: ● Consistent Hematocrit Control :
+Added: Rusfertide has demonstrated durable hematocrit control while reducing phlebotomy needs and avoiding iron deficiency.
+Added: ● Oral Delivery Option :
+Added: PN-8047 provides the convenience of oral administration, potentially improving adherence and patient satisfaction, especially given the chronic nature of PV.
+Added: ● Broad Patient Applicability :
+Added: Both candidates may benefit a wide spectrum of patients, either as monotherapy or in combination with cytoreductive therapies, enabling personalized treatment approaches.
+Added: The PV market represents a rare disease opportunity with significant unmet need.
+Added: Treated patients are often on polytherapy and will cycle through various treatments, including phlebotomy, hydroxyurea, ruxolitinib and/or ropeginterferon.
+Added: Approximately 78% of treated patients do not maintain hematocrit below 45% despite current treatments, and unmet need exists at each step of the treatment landscape.
+Added: Despite standard-of-care treatments, there is a substantial patient population that remains under treated or untreated.
+Added: Rusfertide provides consistent hematocrit control and can potentially reduce treatment burden to achieve a peak revenue potential of $1.0 to $2.0 billion.
+Added: By leveraging non-cytoreductive hepcidin pathway modulation through both injectable and oral delivery, our program seeks to address persistent limitations of current cytoreductive therapies and provide improved hematocrit control for PV patients.
+Added: OUR OBESITY AND METABOLIC DISEASE PROGRAM
+Added: Our obesity and metabolic disease program represents a strategic expansion into one of the largest and fastest-growing therapeutic markets globally.
+Added: We are developing a portfolio of differentiated oral and subcutaneous therapies designed to address significant unmet needs in chronic weight management.
+Added: Our wholly-owned development candidates, PN-477 and PN-458, leverage our proprietary technology platform to target key hormonal and metabolic pathways while addressing persistent barriers to long-term treatment adherence, including gastrointestinal tolerability, the burden of chronic injections, and the potential to support improved body-composition outcomes during weight loss.
+Added: Disease Background and Market Opportunity
+Added: Obesity is a chronic, relapsing metabolic disease characterized by excessive adiposity that impairs health, quality of life, and overall survival.
+Added: It is clinically defined as a body mass index of 30 kg/m² or greater, with severe obesity
+Added: defined as a BMI of 40 kg/m² or greater.
+Added: Globally, over one billion adults are estimated to live with obesity.
+Added: In the United States, nearly 40% of adults meet criteria for obesity and nearly 9% meet criteria for severe obesity.
+Added: Obesity is associated with numerous chronic diseases and comorbidities, including Type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular disease, chronic kidney disease, and obstructive sleep apnea.
+Added: The disease contributes substantially to healthcare utilization and economic burden, including increased direct medical costs and indirect costs associated with lost productivity and disability.
+Added: The global market for anti-obesity medications is experiencing unprecedented growth driven by rising disease prevalence, increasing clinical adoption of pharmacologic interventions, and expanded treatment paradigms.
+Added: The global market for anti-obesity medications is expected to reach more than $120 billion by 2034.
+Added: In the United States, only an estimated 5% of the approximately 131 million Americans with obesity or who are drug-eligible, overweight individuals currently receive pharmacologic treatment, indicating substantial room for market expansion.
+Added: Despite this growth trajectory, discontinuation rates remain high due to tolerability issues, the burden of chronic injections, access limitations, and patient preferences for oral therapies.
+Added: In 2025, Wegovy® and Zepbound® collectively generated tens of billions of dollars in global revenue, underscoring both the commercial potential of the category and the demand for differentiated next-generation therapies.
+Added: Current Therapeutic Landscape and Unmet Medical Needs
+Added: The obesity therapeutic landscape has evolved rapidly over the past several years, expanding beyond traditional lifestyle interventions and bariatric surgery to include pharmacologic therapies with demonstrated effects on body weight and metabolic parameters.
+Added: Injectable incretin-based therapies, particularly GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists, have validated the obesity indication and established proof of concept for hormone-modulating approaches.
+Added: The current market leaders include Novo Nordisk’s Wegovy® (semaglutide), and Eli Lilly’s Zepbound® (tirzepatide), which serve as standards of care for chronic weight management.
+Added: In January 2026, oral Wegovy® (semaglutide) launched in the United States, demonstrating industry recognition of patient demand for oral treatment options.
+Added: Multiple oral candidates from various manufacturers are under regulatory review or in clinical development.
+Added: Additionally, several next-generation multi-receptor agonist therapies and combination approaches targeting GLP-1, GIP, glucagon, amylin, or other pathways are in mid-to-late stages of clinical development, including Eli Lilly's retatrutide, an injectable triple agonist targeting GLP-1, GIP, and glucagon receptors.
+Added: Despite the transformative impact of current GLP-1 and dual agonist therapies, significant unmet medical needs persist:
+Added: ● Route of Administration and Treatment Burden:
+Added: High rates of discontinuation are reported with chronic injectable therapies, driven in part by injection burden, needle aversion, and tolerability issues.
+Added: While oral formulations are beginning to enter the market, options remain limited, particularly for multi-receptor agonist approaches.
+Added: ● Adherence and Durability:
+Added: Long-term medication adherence remains suboptimal for many patients across obesity pharmacotherapies.
+Added: Sustained metabolic benefits beyond active treatment are limited, and weight regain following treatment discontinuation is common, underscoring the chronic nature of obesity and the need for therapies that support sustained adherence.
+Added: ● Quality of Weight Loss:
+Added: Rapid weight reduction achieved with current therapies can result in significant loss of lean muscle mass alongside fat mass.
+Added: This loss of lean muscle mass can negatively affect metabolic health, physical function, and overall treatment outcomes.
+Added: Therapies that preferentially reduce adipose tissue while preserving or enhancing lean muscle mass represent an important area of innovation.
+Added: ● Population Penetration and Access:
+Added: Despite strong clinical evidence and regulatory approvals, a relatively small proportion of adults living with obesity receive pharmacologic therapy.
+Added: Barriers include
+Added: cost, insurance coverage limitations, supply constraints, route of administration preferences, and tolerability concerns.
+Added: Our Development Candidates
+Added: Triple Agonist (GLP-1R/GIPR/GCGR)
+Added: PN-477 is a proprietary peptide designed as a triple agonist of the glucagon-like peptide-1 receptor (“GLP-1R”), glucose-dependent insulinotropic peptide receptor (“GIPR”), and glucagon receptor (“GCGR”).
+Added: This multi-receptor approach is intended to provide comprehensive metabolic benefits by simultaneously addressing appetite regulation, glucose homeostasis, and energy expenditure.
+Added: The glucagon receptor component is designed to support energy expenditure and may help support relative preservation of lean mass during weight loss, which we believe represents a potential differentiator from single- and dual-pathway approaches.
+Added: We have engineered PN-477 with a balanced profile of receptor potencies designed to combine the potential for robust weight-loss potential with favorable gastrointestinal tolerability.
+Added: PN-477 exhibits nanomolar potency for GLP-1R, GIPR and GCGR.
+Added: In preclinical studies using diet-induced obesity mouse models, PN-477 demonstrated dose-proportional body-weight loss of up to approximately 50%, showing comparable or differentiated activity relative to publicly disclosed preclinical data for Eli Lilly’s retatrutide, a triple agonist currently in Phase 3 development.
+Added: We observed preferential fat-mass reduction relative to lean-mass loss in these preclinical studies, which we believe is consistent with glucagon receptor engagement supporting preservation of muscle mass.
+Added: PN-477 has demonstrated oral bioavailability in preclinical studies across multiple species, including mice, rats, dogs, and cynomolgus monkeys, with pharmacokinetic profiles supporting the potential for once-daily oral dosing (PN-477o) and once-weekly subcutaneous dosing (PN-477sc).
+Added: The compound exhibits stability in simulated gastric and intestinal fluids, metabolic stability, and thermostability suitable for commercial development.
+Added: Both PN-477o and PN-477sc are being developed in parallel to provide treatment flexibility and address differing patient and physician preferences.
+Added: Dual Agonist (GLP-1R/GIPR)
+Added: PN-458 is a dual agonist of the GLP-1 and GIP receptors, representing a high-potency approach to the validated dual-agonist mechanism established by tirzepatide (Zepbound®), a leading anti-obesity medication that demonstrated approximately 20% body-weight loss in clinical trials.
+Added: PN-458 demontrates nanomolar potency for both GLP-1R and GIPR and exhibits higher in vitro potency than tirzepatide for both target receptors.
+Added: The enhanced GIPR potency may have implications for gastrointestinal tolerability, as preclinical studies suggest that balanced GIP receptor engagement can mitigate GLP-1-mediated nausea and vomiting.
+Added: PN-458 has demonstrated favorable preclinical proof of concept in diet-induced obesity mouse models, showing activity comparable to tirzepatide.
+Added: The compound has demonstrated oral bioavailability in preclinical studies across multiple species with pharmacokinetic profiles supporting the potential for once-daily oral dosing (PN-458o) and once-weekly subcutaneous dosing (PN-458sc).
+Added: As with PN-477, both formulations are being developed in parallel to maximize treatment optionality.
+Added: Strategic Rationale
+Added: We are advancing PN-477 and PN-458 as part of a strategic expansion into obesity and metabolic disease to address these gaps in the obesity treatment landscape through differentiated mechanisms of action and flexible dosing options.
+Added: Our obesity and metabolic disease program is designed to create a diversified portfolio that addresses different patient populations and treatment paradigms:
+Added: ● Optimizing Weight Loss Quality:
+Added: PN-477’s triple-agonist design, incorporating glucagon receptor engagement, is intended to support energy expenditure and fat oxidation while addressing appetite
+Added: regulation and glycemic control.
+Added: The objective is to preferentially reduce adipose tissue relative to lean mass, which may translate to improved metabolic health outcomes and physical function compared to therapies that do not incorporate glucagon pathway activation.
+Added: ● Oral Delivery Optionality:
+Added: Both candidates are being developed with oral formulations designed to align with patient preferences and reduce barriers associated with chronic injections.
+Added: Given the chronic nature of obesity and the need for long-term therapy, oral options have the potential to improve adherence and expand the addressable patient population.
+Added: Offering both oral and subcutaneous formulations of the same active compound provides flexibility for physicians and patients to tailor treatment across different phases of care.
+Added: ● Induction and Maintenance Strategies:
+Added: Parallel oral and subcutaneous development supports potential treatment strategies that utilize subcutaneous administration during initial weight-loss phases, followed by transition to oral maintenance therapy for sustained weight management.
+Added: This approach could address both the acute objective of achieving clinically meaningful weight loss and the chronic requirement of maintaining that weight loss over time.
+Added: ● Portfolio Breadth:
+Added: PN-458 offers a high-potency dual agonist approach for standard weight management needs, leveraging the proven efficacy of the GLP-1/GIP mechanism while providing oral and subcutaneous options that differentiate it from currently available therapies.
+Added: PN-477 provides a broader multi-receptor option with the potential for advantages for patients with more complex metabolic needs or those requiring enhanced preservation of lean muscle mass.
+Added: This portfolio breadth positions us to address both initial weight loss induction and long-term weight maintenance across a range of obesity severities and patient phenotypes.
+Added: The obesity and metabolic disease market is among the most rapidly expanding in contemporary therapeutics, driven by epidemiology, unmet medical need, and the emergence of hormone-modulating drugs with demonstrated clinical benefit.
+Added: By leveraging oral delivery and multi-receptor mechanisms, our program seeks to address persistent limitations of current therapies and deliver differentiated solutions across this large and growing market.
+Added: OUR PROPRIETARY TECHNOLOGY PLATFORM
Our proprietary technology platform is purposefully built to exploit the advantages of constrained peptides, which are much smaller than antibody-based drugs and may be delivered orally but are big enough to bind and block the difficult targets that antibodies bind and modulate.
2 unchanged sentences
We apply this platform to the discovery and development of constrained peptides as new drug candidates.
−Removed: The platform is used to develop potential drug candidates (agonists and antagonists):
−Removed: (i) using the structure of a target, when available, (ii) de novo when no target structure exists, or (iii) from publicly disclosed peptide starting points.
−Removed: In a structure-based approach, our proprietary molecular design software and structural database of several thousand constrained peptides, termed Vectrix™, are screened to identify suitable scaffolds.
−Removed: The scaffolds identified form the basis of designing and constructing the first set of phage or chemical libraries.
−Removed: The initial hits are identified by either panning or screening such libraries, respectively.
−Removed: When structural information is unavailable for a target, hits are identified by panning a set of 34 proprietary cluster-based phage libraries consisting of millions of constrained peptides.
−Removed: Once the hits are identified, they are optimized using a set of peptide, peptide mimetic and medicinal chemistry techniques that include the incorporation of new or manipulation of existing cyclization-constraints, as well as natural or unnatural amino acids and chemical conjugation or acylation techniques.
−Removed: These techniques are applied to optimize potency, selectivity, stability, exposure and ultimately efficacy.
For rusfertide, hit discovery and optimization relied exclusively on medicinal and computational chemistry, with no phage display, to develop potent and selective injectable candidates with enhanced stability and exposure in blood.
For injectable products, stability in blood is determined using in vitro assay techniques to identify chemical and biological sites of degradation, which are then optimized while still maintaining potency and selectivity.
−Removed: Conjugation strategies are used to optimize the exposure of the injected peptide.
−Removed: For icotrokinra, phage display is tightly coupled to medicinal chemistry, structural biology and oral stability techniques to develop potent, selective and orally delivered molecules.
−Removed: Oral stability is profiled in a series of in vitro and ex vivo assays that portray the chemical and metabolic barriers a peptide will encounter as it transits the GI and systemic compartments as needed.
−Removed: These metabolically labile spots in the peptides are optimized using medicinal chemistry-based approaches to engineer oral stability while maintaining selectivity and potency.
−Removed: Various in vivo pharmacology tools are then used to quantify peptide exposure in relevant GI and systemic compartments.
−Removed: This data can be used to optimize required exposure over the required time frame to achieve in vivo efficacy.
−Removed: This is complemented by formulation technologies to enhance GI and systemic exposure by exploiting the intrinsic stability of our oral peptides.
−Removed: Finally, various biomarkers are also developed to correlate exposure with efficacy to guide candidate selection, dose selection and provide preliminary POC of target engagement in clinical trials.
+Added: For Icotyde, phage display is tightly coupled to medicinal chemistry, structural biology and oral stability techniques to develop potent, selective and orally delivered molecules.
Discovery and Pre-clinical Activities
We believe we have built a versatile, well-validated and unique discovery platform.
−Removed: For example, this peptide technology platform has been used to develop product candidates for diverse target classes including G-protein-coupled receptors, ion channels, transporters, cytokines and their receptors for a variety of therapeutic areas.
−Removed: In the future we may tackle other I&I, metabolic and blood disorders and expand our technology platform to provide potential opportunities to pursue a wider variety of diseases that may include oral, topical and systemic approaches.
+Added: For example, this technology platform has been used to develop product candidates for diverse target classes including G-protein-coupled receptors, ion channels, transporters, cytokines and their receptors for a variety of therapeutic areas.
+Added: In the future we may tackle
+Added: other I&I, blood and metabolic disorders and expand our technology platform to provide potential opportunities to pursue a wider variety of diseases that may include oral, topical and systemic approaches.
+Added: Our integrated medicinal chemistry and computational capabilities also enable us to pursue small molecule discovery and development for biological targets where high oral bioavailability is required for effective therapies.
+Added: An example of this approach is the discovery of PN-8047, an oral hepcidin functional mimetic.
We also intend to progress our platform to achieve systemic bioavailability and activity with oral peptides, macrocycles and peptidomimetics, thereby enabling us to address systemic diseases.
−Removed: Examples of this approach are the discovery and development of icotrokinra, our IL-23R antagonist in collaboration with JNJ, and PN-881, our recently announced IL-17 peptide antagonist product candidate, as described above.
+Added: Examples of this approach are the discovery and development of Icotyde, our IL-23R antagonist in collaboration with JNJ, and PN-881, our wholly-owned Phase 1 IL-17 oral peptide antagonist, as described above.
The biotechnology and pharmaceutical industries are intensely competitive and subject to rapid and significant technological change.
While we believe that our product candidates, technology, knowledge and experience provide us with certain competitive advantages, we face competition from established and emerging pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions, among others.
−Removed: Ruxolitinib, marketed as Jakafi®, was approved in 2014 for the treatment of adults with PV who have inadequate response to or are intolerant to hydroxyurea.
−Removed: Approximately 5,300 PV patients are treated with Jakafi® each year.
−Removed: Besremi®, a ropeginterferon alfa-2b product indicated for the treatment of adults with PV, was approved with a black box warning in November 2021.
−Removed: We are aware of other investigational compounds under clinical development for treatment of PV, including short interfering RNA approaches aimed at modulating or increasing endogenous hepcidin levels.
−Removed: In psoriasis and PsA, competition will come from companies with approved injectable agents in the IL-17 and IL-12/23 pathway, including Cosentyx®, Taltz®, Siliq®, Tremfya®, and Skyrizi®.
−Removed: Bimekizumab (anti-IL-17A and F, UCB) has completed a positive Phase 3 program in psoriasis.
+Added: In psoriasis and PsA, competition will come from companies with approved injectable agents in the IL-17 and IL-12/23 pathway, including Cosentyx® (Novartis), Taltz® (Eli Lilly), Siliq® (Bausch Health), Tremfya® (Johnson & Johnson), and Skyrizi® (AbbVie).
+Added: Bimekizumab (Bimzelx ®, UCB), an anti- IL-17A and F antibody, was approved for psoriasis in 2023 and for PsA in 2024.
Otezla® (Amgen) was the first oral agent approved in both psoriasis and PsA.
−Removed: The oral JAK inhibitors Xeljanz® (Pfizer) and Rinvoq® are approved in PsA.
−Removed: Several oral small molecules that inhibit the Janus kinase TYK2 are advancing in development.
−Removed: The Bristol Myers Squibb (“BMS”) TYK2 inhibitor, Sotyktu®, was approved for psoriasis in 2022.
−Removed: Second generation allosteric TYK2 inhibitors from Nimbus Therapeutics (recently in-licensed by Takeda) are moving into Phase 3 development, and a molecule from Ventyx Biosciences has initiated Phase 2 development.
−Removed: Several small molecules that inhibit IL-17 have completed Phase 1 development.
−Removed: In IBD, competition will come from companies with injectable agents in the anti-integrin class (Entyvio®, Takeda, approved) and the anti-IL-12/23 class that may be approved in the next several years, including JNJ’s Stelara® (approved in UC and CD), Abbvie’s risankizumab (Skyrizi®) (UC and CD Phase 3), JNJ’s guselkumab (Tremfya®) (UC and CD);
−Removed: and Eli Lilly’s mirikizumab (Omvoh®) (UC and CD).
−Removed: In addition, orally delivered agents with novel mechanisms of action that are approved for or in development and may be approved for UC and/or CD prior to or shortly after the launch of our product candidates can have significant impact in the competitive environment, including:
−Removed: ● JAK inhibitors:
−Removed: The pan-JAK tofacitinib (Xeljanz®) is approved in UC.
−Removed: The next-generation selective JAK1/3 inhibitors, including Abbvie’s upadacitinib (Rinvoq®), were approved in UC and CD in 2022.
−Removed: Pfizer’s selective JAK1/TEC inhibitor ritlecitinib is in Phase 2 development for UC and CD;
−Removed: ● S1P1 receptor modulators:
−Removed: BMS’s ozanimod (Zeposia®) and Pfizer’s etrasimod (Velsipity®) are approved in UC.
−Removed: Etrasimod is being studied in CD, though ozanimod was not found to show efficacy in CD;
−Removed: ● Eli Lilly is developing MORF-057, an oral small molecule targeting α4β7, which is progressing in Phase 2 development in UC and CD.
−Removed: Other oral small molecules targeting α4β7 from Gilead and Ensho Therapeutics are in early clinical development.
−Removed: Many other agents are in early-stage development in IBD, including injectable anti-TLIA antibodies by Pfizer and Merck, and Teva and Sanofi which have recently presented positive Phase 2 results in IBD.
−Removed: In competitive areas, we believe there is a strong need for a differentiated oral approach.
−Removed: The injectable mAbs Cosentyx and Taltz targeting IL-17 AA and AF are approved in psoriasis, PsA, and SpA.
−Removed: Cosentyx was also recently the first IL-17 inhibitor approved in HS.
−Removed: Siliq, a mAb to the IL-17 receptor, is approved in psoriasis only and carries a black box warning for suicidal ideations.
−Removed: Bimzelx is a mAb that targets IL-17 AA, AF and FF.
−Removed: It is approved in psoriasis, PsA, HS, SS and nr-axSpA.
−Removed: Sonelokimab (MoonLake) is an injectable nanobody with IL-17 AA, AF and FF activity and has demonstrated POC in Phase 2 in psoriasis, PsA, and HS.
−Removed: There are several oral IL-17 small molecules in clinical development with the most advanced, DC-853 (Lilly via acquisition of DICE Therapeutics) in a Phase 2b trial in psoriasis.
−Removed: JNJ and Sanofi are also developing small molecules.
+Added: The oral JAK inhibitors Xeljanz® (Pfizer) and Rinvoq® (AbbVie) are approved in PsA.
+Added: Several oral TYK2 inhibitors are advancing in development.
+Added: Bristol Myers Squibb’s Sotyktu® was approved for psoriasis in 2022.
+Added: Second-generation allosteric TYK2 inhibitors include zasocitinib (TAK-279, Takeda) and envudeucitinib (ESK-001, Alumis), which both reported positive Phase 3 results in late 2025 and early 2026, and are moving toward regulatory submissions for psoriasis and PsA.
+Added: In IBD, competition includes approved injectable anti-integrin agents, such as Entyvio® (Takeda), and anti-IL-12/23 agents, including Stelara® (Johnson & Johnson), Skyrizi® (AbbVie), Tremfya® (Johnson & Johnson), and Omvoh® (Eli Lilly), all of which are now approved for both UC and CD.
+Added: Oral agents approved or in development include JAK inhibitors Xeljanz® (approved in UC) and Rinvoq® (approved in UC and CD), with Pfizer's ritlecitinib in Phase 2 for both indications.
+Added: S1P receptor modulators Zeposia® and Velsipity® are approved for UC, with Velsipity currently undergoing Phase 3 evaluation for CD.
+Added: A new class of oral α4β7 integrin inhibitors is emerging, with Eli Lilly's MORF-057 in Phase 2b for UC, alongside candidates GS-1427 (Gilead) and NSHO-101 (Ensho Therapeutics) in mid-stage clinical development.
+Added: In competitive areas, we believe there continues to be a strong need for a differentiated oral approach.
+Added: Injectable monoclonal antibodies targeting the IL-17 pathway are well established across multiple inflammatory indications.
+Added: Cosentyx® and Taltz®, monoclonal antibodies targeting IL-17A, are approved in psoriasis, PsA, and spondyloarthritis, and Cosentyx is also approved in HS.
+Added: Siliq®, a monoclonal antibody targeting the IL-17 receptor, is approved in psoriasis only and carries a boxed warning for suicidal ideation and behavior.
+Added: Bimzelx® (bimekizumab), a monoclonal antibody targeting IL-17A, IL-17F, and the IL-17A/F heterodimer, is approved in multiple indications, including psoriasis, PsA, HS, and axSpA.
+Added: Sonelokimab (MoonLake), an investigational injectable nanobody with activity against IL-17A, IL-17F, and the IL-17A/F heterodimer, has reported clinical data in late-stage trials and continues in clinical development.
+Added: In the oral space, we are aware of small-molecule and peptide inhibitors in clinical development.
+Added: DC-853 (LY4100511), an oral IL-17 small molecule being evaluated by Eli Lilly, has advanced into Phase 2 clinical
+Added: investigation.
+Added: ASC50 (Ascletis Pharma) has reported positive Phase 1 results.
+Added: Emerging oral macrocyclic peptides, including PeptiDream’s dual IL-17A/IL-17F candidate, are also entering early clinical development and may add to competition in this space.
+Added: Rusfertide & PN-8047
+Added: In the treatment of PV, competition includes therapies with differing mechanisms of action.
+Added: Ruxolitinib, marketed as Jakafi® (Incyte), was approved in 2014 for adults with PV who are intolerant of or have an inadequate response to hydroxyurea.
+Added: Besremi® (ropeginterferon alfa-2b-nicotinamide, PharmaEssentia/AOP), indicated for adults with PV, was approved in November 2021 and carries a black box warning.
+Added: We compete with companies developing targeted therapies for PV, including monoclonal antibodies, RNA-based therapies, and small molecules.
+Added: Several programs are in late-stage development, including bomedemstat (Merck/Imago) and givinostat (Italfarmaco), which represent potential oral alternatives for PV management.
+Added: We also face competition from therapies that aim to modulate iron levels or hepcidin activity to control RBC production.
+Added: These include divesiran (Silence Therapeutics), a siRNA targeting TMPRSS6 in Phase 2, and DISC-3405 (Disc Medicine), a monoclonal antibody targeting TMPRSS6 in Phase 2.
+Added: Additional RNA-based programs include sapablursen (Ionis Pharmaceuticals) and investigational therapies from Alnylam Pharmaceuticals.
+Added: CSL Vifor is developing vamifeport, an oral ferroportin inhibitor.
+Added: PN-477 & PN-458
+Added: In obesity and weight management, competition consists of approved injectable incretin-based therapies and a rapidly expanding pipeline of oral small molecules, multi-receptor agonists, and alternative metabolic pathways, including amylin- and glucagon-based approaches.
+Added: Competition is led by glucagon-like peptide-1 (“GLP-1”) and glucose-dependent insulinotropic polypeptide (“GIP”) receptor agonists.
+Added: Approved injectable therapies include Wegovy® (semaglutide, Novo Nordisk) and Zepbound® (tirzepatide, Eli Lilly).
+Added: In December 2025, the FDA approved oral Wegovy® (Novo Nordisk) for chronic weight management.
+Added: The competitive landscape is expanding to include multi-receptor agonists, including triple agonists targeting GLP-1, GIP, and glucagon, as well as dual-acting combination approaches.
+Added: Retatrutide (Eli Lilly) is a triple-receptor agonist that has reported positive Phase 3 clinical results.
+Added: CagriSema, a once-weekly injectable fixed-dose combination of semaglutide and the amylin analog cagrilintide (Novo Nordisk), has been submitted for regulatory approval.
+Added: MariTide (maridebart cafraglutide, Amgen) is a bispecific peptide-antibody conjugate that activates the GLP-1 receptor while antagonizing the GIP receptor and is being evaluated in a Phase 3 clinical program.
+Added: VK2735 (Viking Therapeutics) is a dual GLP-1/GIP receptor agonist in Phase 3 development for subcutaneous administration, with an oral formulation in mid-stage clinical development.
+Added: Several companies are developing non-peptide oral incretin therapies and other next-generation oral candidates.
+Added: Orforglipron (Eli Lilly) is an oral, non-peptide GLP-1 receptor agonist under regulatory review.
+Added: Aleniglipron (Structure Therapeutics) is an oral GLP-1 receptor agonist that has completed Phase 2 clinical development.
+Added: Pfizer, which completed its acquisition of Metsera in 2025, is developing next-generation oral and peptide-based incretin therapies for obesity and related cardiometabolic conditions.
+Added: In addition to incretin-based approaches, modalities targeting the amylin pathway are being developed as standalone and combination therapies.
+Added: Amycretin (Novo Nordisk) is a single-molecule agonist of both GLP-1 and amylin receptors in late-stage clinical development, including oral and subcutaneous formulations.
+Added: Petrelintide (Zealand Pharma, in collaboration with Roche) is a long-acting amylin analog in mid-stage clinical development.
+Added: Other emerging approaches include dual GLP-1/glucagon receptor agonists, such as survodutide (Boehringer Ingelheim) and pemvidutide (Altimmune).
+Added: Additional early-stage programs are exploring alternative gut hormone pathways, novel peptide delivery technologies, and centrally mediated mechanisms of appetite and metabolism.
+Added: While many of these programs remain in early development, they may further intensify competition in the obesity treatment landscape.
Material Agreements
1 unchanged sentence
In January 2024, we entered into the Takeda Collaboration Agreement.
−Removed: See Part II, Item 7, “Management’s Discussion and Analysis – Overview” and Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
+Added: See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
JNJ License and Collaboration Agreement
−Removed: On July 27, 2021, we entered into an Amended and Restated License and Collaboration Agreement (the “JNJ License and Collaboration Agreement”) with JNJ, which amended and restated the License and Collaboration Agreement, effective July 13, 2017, by and between us and JNJ (the “Original Agreement”), as amended by the first amendment, effective May 7, 2019 (the “First Amendment”).
−Removed: The JNJ License and Collaboration Agreement, which relates to the development, manufacture and commercialization of oral IL-23 receptor antagonist drug candidates and enables JNJ to develop collaboration compounds for multiple indications, was further amended in November 2024.
−Removed: See Part II, Item 7, “Management’s Discussion and Analysis – Overview” and Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
+Added: In July 2017, we entered into the JNJ License and Collaboration Agreement.
+Added: See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
Research Collaboration and License Agreement with Zealand Pharma A/S
In June 2012, we entered into a Research Collaboration and License Agreement (the “Zealand Agreement”) with Zealand Pharma A/S (“Zealand”) to identify, optimize and develop novel disulfide-rich peptides to discover a hepcidin mimetic.
−Removed: We amended this agreement on February 28, 2014, at which point we assumed responsibility for the development program.
+Added: We amended this agreement in February 2014, at which point we assumed responsibility for the development program.
See Part II, Item 7.
2 unchanged sentences
We strive to protect and enhance the proprietary technology, inventions, and improvements that are commercially important to the development of our business, including seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties.
−Removed: We also rely on trade secrets relating to our proprietary technology platform and on know-how, and continuing technological innovation to develop, strengthen, and maintain our
−Removed: proprietary position in the field of peptide-based therapeutics that may be important for the development of our business.
+Added: We also rely on trade secrets relating to our proprietary technology platform and on know-how, and continuing technological innovation to develop, strengthen, and maintain our proprietary position in the field of peptide-based therapeutics that may be important for the development of our business.
We will also take advantage of regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available.
6 unchanged sentences
For more information, please see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.”
−Removed: We own or co-own 30 issued U.S.
+Added: We own or co-own over 30 issued U.S.
patents, over 80 granted ex-U.S.
3 unchanged sentences
Our proprietary intellectual property, including patent and non-patent intellectual property, is generally directed to, for example, peptide-based therapeutic compounds and compositions, methods of using these peptide-based therapeutic compounds and compositions to treat or prevent disease, methods of manufacturing peptide-based therapeutic compounds and compositions, and other proprietary technologies and processes related to our lead product development candidates.
−Removed: Specific patents and patent applications are directed to compositions of α 4 β7 integrin peptides, IL-23R antagonist peptides, IL-17 antagonist peptides and hepcidin mimetics peptides, as well as methods of synthesizing and using these peptides to treat disorders.
+Added: Specific patents and patent applications are directed to compositions of α 4 β7 integrin peptides, IL-23R antagonist peptides, IL-17 antagonist peptides, hepcidin mimetics peptides and small molecules, and glucagon superfamily receptor agonists, as well as methods of synthesizing and using these compounds to treat disorders.
Applications are currently pending in the United States and other major jurisdictions, including Australia, Canada, China, Japan, and Europe.
−Removed: We expect our patents and patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire from October 2033 to December 2044 (excluding possible patent term extensions).
+Added: expect our patents and patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire from October 2033 to September 2045 (excluding possible patent term extensions).
Our objective is to continue to expand our portfolio of patents and patent applications in order to protect our clinical assets and related peptide-based drug technologies.
14 unchanged sentences
A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended.
−Removed: Moreover, a patent can only be extended
−Removed: once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product.
+Added: Moreover, a patent can only be extended once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product.
Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug.
8 unchanged sentences
To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.
−Removed: For more information, please see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.”
+Added: For more information, see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.”
Manufacturing
4 unchanged sentences
We work with contract manufacturers in the United States, Europe and Asia.
−Removed: Although we rely on contract manufacturers, our personnel and consultants have extensive manufacturing and quality control experience overseeing CMOs.
+Added: Although we rely on contract manufacturers, our
+Added: personnel and consultants have extensive manufacturing and quality control experience overseeing CMOs.
We regularly consider second source or back-up manufacturers for both API and drug product manufacturing.
2 unchanged sentences
We currently engage CMOs on a “fee for services” basis for our current development and clinical supplies.
+Added: JNJ is responsible for the manufacturing of Icotyde pursuant to the JNJ License and Collaboration Agreement.
+Added: Takeda is responsible for the manufacturing of rusfertide pursuant to the Takeda Collaboration Agreement.
Government Regulation
3 unchanged sentences
In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act and its implementing regulations.
−Removed: The process of obtaining regulatory approvals and the compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
+Added: The process of obtaining regulatory approvals and compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
Failure to comply with the applicable U.S.
7 unchanged sentences
● satisfactory completion of an FDA advisory committee review, if applicable;
−Removed: ● satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMP”) requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;
+Added: ● satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMP”)
+Added: requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;
● satisfactory completion of an FDA inspection of one or more clinical trial sites to assure compliance with GCP requirements and the clinical protocol;
3 unchanged sentences
These pre-clinical studies must comply with GLP.
+Added: In April 2025, the FDA published a roadmap to reduce animal testing in preclinical safety studies, including those required in INDs, with scientifically validated new approach methodologies.
An IND sponsor must submit the results of the pre-clinical tests, together with manufacturing information, analytical data and any available clinical data or literature to the FDA as part of an IND.
34 unchanged sentences
An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions.
−Removed: The FDA is not bound by
−Removed: the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
+Added: The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured.
8 unchanged sentences
It may also require that contraindications, warnings or precautions be included in the product labeling or require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval.
−Removed: In addition, the FDA may mandate testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS.
+Added: In addition, the
+Added: FDA may mandate testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS.
This can materially affect the potential market and profitability of the product.
16 unchanged sentences
After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.
−Removed: biologics with orphan designation are not subject to a PDUFA fee upon the submission of an NDA.
+Added: Drugs or biologics with orphan designation are not subject to a PDUFA fee upon the submission of an NDA.
Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.
8 unchanged sentences
As a result, the scope of exclusivity was interpreted as preventing approval of a competing product.
−Removed: However, in 2021, the federal court in Catalyst Pharmaceuticals, Inc.
+Added: However, in 2021, the federal
+Added: court in Catalyst Pharmaceuticals, Inc.
Becerra, suggested that orphan drug exclusivity covers the full scope of the orphan-designated “disease or condition” regardless of whether a drug obtained approval for a narrower use.
39 unchanged sentences
Decreases in third-party reimbursement for our product candidates or a decision by a third-party payor to not cover our product candidates could reduce physician usage of our products candidates, once approved, and have a material adverse effect on our sales.
−Removed: The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, collectively referred to as the ACA, enacted in March 2010, has had and is expected to continue to have a
−Removed: significant impact on the health care industry.
+Added: The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, collectively referred to as the ACA, enacted in March 2010, has had and is expected to continue to have a significant impact on the health care industry.
The ACA imposes a significant annual fee on certain companies that manufacture or import branded prescription drug products.
2 unchanged sentences
There have been executive, judicial and Congressional challenges to certain aspects of the ACA.
−Removed: For example, President Trump signed several Executive Orders and other directives designed to delay the implementation of certain ACA requirements or otherwise circumvent some of the health insurance mandates.
+Added: For example, there have been several Executive Orders and other directives designed to delay the implementation of certain ACA requirements or otherwise circumvent some of the health insurance mandates.
Concurrently, Congress considered legislation to repeal or repeal and replace all or part of the ACA.
3 unchanged sentences
The Bipartisan Budget Act of 2018 amends the ACA to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole,” and increase from 50% to 70% the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in the Medicare Part D program.
−Removed: The Inflation Reduction Act (“IRA”), enacted August 16, 2022, aims to control prescription drug prices in the upcoming years.
+Added: The Inflation
+Added: Reduction Act (“IRA”), enacted August 16, 2022, aims to control prescription drug prices in the upcoming years.
The IRA will allow the Centers for Medicare & Medicaid Services (“CMS”) to cap out-of-pocket costs in 2025 and to negotiate prescription drug prices in 2026 for the first time.
Additionally, the IRA provides a new “inflation rebate” covering Medicare patients beginning in 2023 to prevent rapid and arbitrary price increases in prescription drugs.
−Removed: These and any other legislation or healthcare reform measures of the Biden administration may impact the ACA and our business.
+Added: These and any other legislation or healthcare reform measures may impact the ACA and our business.
There may also be further challenges to the ACA, and new laws may also result in additional reductions in Medicare and other health care funding.
1 unchanged sentence
This scrutiny has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.
−Removed: At the federal level, the Trump administration implemented drug pricing reform through federal budget proposals, executive orders and policy initiatives.
−Removed: For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing that attempt to implement several of the administration’s proposals The FDA also released a final rule, effective November 30, 2020, implementing a portion of the importation executive order providing guidance for states to build and submit importation plans for drugs from Canada.
−Removed: Further, on November 20, 2020, the U.S.
−Removed: Department of Health and Human Services (“HHS”) finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
−Removed: The implementation of the rule was delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.
−Removed: The rule also creates a safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.
+Added: At the federal level, the current administration implemented drug pricing reform through federal budget proposals, executive orders and policy initiatives.
+Added: In May 2025, the current administration renewed the idea of international reference pricing through an executive order entitled “Delivering Most-Favored-Nation Prescription Drug Pricing to American Patients,” which, among other things, directs the U.S.
+Added: Department of Health and Human Services (the “HHS”) and other agencies to communicate most-favored-nation price targets to pharmaceutical manufacturers to bring prices for U.S.
+Added: patients in line with comparably developed nations and to facilitate direct-to-consumer purchasing programs.
+Added: The HHS subsequently issued guidance indicating the most-favored-nation (“MFN”) target price will be the lowest price paid in an Organisation for Economic Co-operation and Development country with a gross domestic product (“GDP”) per capita of at least 60% of the U.S.
+Added: GDP per capital.
+Added: In addition, in December 2025, CMS proposed new drug payment models to lower drug prices for Medicare beneficiaries;
+Added: under the models, CMS would explore potential adjustments to Medicare drug inflation rebate calculations by comparison to international drug pricing information.
+Added: It is currently unclear whether and to what extent these measures will be implemented and what impact any such implementation would have on our business.
Federal and state legislatures have become increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
1 unchanged sentence
It is uncertain whether and how future legislation, whether domestic or foreign, could affect prospects for our product candidates or what actions payors for health care treatment and services may take in response to such health care reform proposals or legislation.
−Removed: Adoption of price controls and other cost-containment measures, and adoption of more
−Removed: restrictive policies in jurisdictions with existing controls and measures reforms may prevent or limit our ability to generate revenue, attain profitability or commercialize our product candidates.
+Added: Adoption of price controls and other cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures reforms may prevent or limit our ability to generate revenue, attain profitability or commercialize our product candidates.
Other Health Care Laws and Compliance Requirements
3 unchanged sentences
the Anti-Kickback Statute, which prohibits persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal health care programs such as the Medicare and Medicaid programs;
−Removed: federal false claims laws and civil monetary penalties laws that prohibit any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid;
+Added: federal false claims laws and civil monetary penalties laws that prohibit any person or entity from knowingly
+Added: presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid;
and the Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the CMS information related to payments and other transfers of value made to various healthcare professionals including physicians, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, certified nurse-midwives and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.
16 unchanged sentences
Under the CTR, a sponsor may submit a single application for approval of a clinical trial through a centralized EU clinical trials portal.
−Removed: One national regulatory authority (the reporting EU Member State proposed by the applicant) will take the lead in validating and evaluating the application consult and coordinate with the other concerned Member States.
+Added: One national regulatory authority (the reporting EU Member State proposed by the applicant) will take the lead in validating and evaluating the application and consult and coordinate with the other concerned Member States.
If an application is rejected, it may be amended and resubmitted through the EU clinical trials portal.
If an approval is issued, the sponsor may start the clinical trial in all concerned Member States.
−Removed: However, a concerned EU Member State may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such Member State.
+Added: However, a concerned EU
+Added: Member State may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such Member State.
The CTR also aims to streamline and simplify the rules on safety reporting and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical trial results to the EU Database (“CTIS”).
−Removed: Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive will need to comply with the CTR and have to be transitioned to CTIS.
+Added: Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive need to comply with the CTR and have to be transitioned to CTIS.
National laws, regulations, and the applicable GCP and Good Laboratory Practice standards must also be respected during the conduct of the trials, including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (“ICH”) guidelines on GCP and the ethical principles that have their origin in the Declaration of Helsinki.
3 unchanged sentences
The centralized procedure provides for the grant of a single MA that is issued by the European Commission (“EC”) following the scientific assessment of the application by the EMA that is valid for all EU Member States as well as in the three additional EEA Member States.
−Removed: The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineered medicines), and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune and viral diseases).
+Added: The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineered medicines), and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other dysfunctions, and viral diseases).
For medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that constitute significant therapeutic, scientific or technical innovations or for which the grant of an MA through the centralized procedure would be in the interest of public health at EU level, an applicant may voluntarily submit an application for an MA through the centralized procedure.
1 unchanged sentence
The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA.
−Removed: Under the centralized procedure, the timeframe for the evaluation of an MAA by the CHMP is, in principle, 210 days
−Removed: from receipt of a valid MAA.
+Added: Under the centralized procedure, the timeframe for the evaluation of an MAA by the CHMP is, in principle, 210 days from receipt of a valid MAA.
However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically takes a year or more, unless the application is eligible for an accelerated assessment.
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European Data Protection Laws
−Removed: The collection and use of personal health data and other personal data in the EU is governed by the provisions of the European General Data Protection Regulation (EU) 2016/679 (“GDPR”) and related data protection laws in individual EU Member States.
−Removed: The GDPR imposes strict requirements on the processing of personal data, including the legal basis for the processing, the information that has to be provided to individuals before their data is processed,
−Removed: personal data breaches which may have to be notified to national data protection authorities and data subjects, the measures to be taken when engaging processors, and the technical and organization measures to ensure the security and confidentiality of the personal data.
−Removed: EU Member States may also have additional requirements for health, genetic, and biometric data through their national legislation.
−Removed: The GDPR also imposes restrictions on the transfer of personal data to countries outside of the EU that do not provide an adequate level of data protection.
+Added: The processing of personal data, including health-related personal data in the European Economic Area (“EEA”) is mainly governed by the provisions of the European General Data Protection Regulation (EU) 2016/679 (“GDPR”) and related data protection laws in individual EEA countries.
+Added: In the United Kingdom, the processing of personal data is mainly governed by the GDPR as incorporated into UK law pursuant to the European Union (Withdrawal) Act 2018 (the “UK GDPR”).
+Added: The GDPR and UK GDPR impose strict requirements on the processing of personal data, including the legal basis for the processing, the information that has to be provided to individuals before their data is processed, personal data breaches which may have to be notified to national data protection authorities and data subjects, the measures to be taken when engaging processors, and the technical and organization measures to ensure the security and confidentiality of the personal data.
+Added: EEA countries may also have additional requirements for the processing of health, genetic, and biometric data through their national legislation.
+Added: The GDPR also imposes restrictions on the transfer of personal data to countries outside of the EEA that do not provide an adequate level of data protection.
To enable such transfers, appropriate safeguards, such as standard contractual clauses (“SCCs”) must be in place.
−Removed: When relying on SCCs, data exporters are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the SCCs in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence.
+Added: When relying on the appropriate safeguards, data exporters, with the assistance of the data importers, are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the safeguards in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence.
Where no supplementary measure is suitable, the data exporter should avoid, suspend or terminate the transfer.
Alternatively, such transfers can be based on an adequacy decision by the EU commission.
−Removed: Regarding transfers to the US, the EU commission issued an adequacy decision for transfers to companies that are certified under the new EU-US Data Privacy Framework, which entered into force on June 10, 2023.
−Removed: Failure to comply with the requirements of the GDPR and the related national data protection laws of the EU Member States may result in significant monetary fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater, other administrative penalties and a number of criminal offenses for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed.
+Added: Regarding transfers to the United States, the EU commission issued an adequacy decision for transfers to companies that are certified under the new EU-US Data Privacy Framework, which entered into force on June 10, 2023.
+Added: Under the adequacy decision, personal data can flow from the EEA to U.S.
+Added: companies participating in the framework.
+Added: Failure to comply with the requirements of the GDPR or UK GFPR and the related national data protection laws of the EEA countries may result in significant monetary fines for noncompliance of up to €20 million or £17.5 million (as applicable), or 4% of the total worldwide annual turnover (for higher-tier infringements).
+Added: This is enforced by the UK Information Commissioner’s Office (“ICO”) and is entirely separate from fines under EU GDPR.
+Added: In addition, violations of national laws can trigger additional, administrative penalties, investigations, corrective orders, temporary or definitive bans, and in some jurisdictions, a number of criminal offenses for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed.
Sustainability, Corporate Responsibility and Human Capital Disclosures
16 unchanged sentences
We also support educational efforts related to therapeutic areas in focus for our company, and life sciences education more broadly.
−Removed: In addition to financial support of continuing
−Removed: education, we are active sponsors, mentors, and hosts for students seeking to broaden their understanding of life sciences in the interest of advancing human health.
+Added: In addition to financial support of continuing education, we are active sponsors, mentors, and hosts for students seeking to broaden their understanding of life sciences in the interest of advancing human health.
Human Capital
We recognize that our success is driven by the knowledge, skills and dedication of our employees.
−Removed: Our human capital is fundamental to our ability to innovate and develop life-changing peptide drug therapies.
+Added: Our human capital is fundamental to our ability to innovate and develop life-changing drug therapies.
We invest in our employees by seeking to foster a supportive and inclusive workplace.
1 unchanged sentence
As of December 31, 2025, our total global workforce consisted of 132 full-time equivalent employees, 103 of whom were in research and development.
−Removed: The remaining 28 employees worked in finance, legal, business development, human resources, information technology (“IT”) and administrative support.
+Added: The remaining 29 employees worked in finance, legal, business development,
+Added: human resources, information technology (“IT”) and administrative support.
123 of our full-time equivalent employees are located in the United States and 9 are located in Australia.
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employees’ monthly healthcare premiums.
−Removed: For the year ended December 31, 2024, our employee turnover rate was approximately 11%.
We have a performance development review process in which managers provide regular feedback to assist with the development of our employees, including the use of individual plans to assist with career development.
We also invest in the growth and development of our employees through various training and development programs that help build and strengthen our employees’ leadership and professional skills.
−Removed: This reflects the quality and readiness of our people to take on new roles, as well as our intentional focus on growing and developing careers, as well as promoting from within.
+Added: This reflects the quality and readiness of our people to take on new roles, as well as our intentional focus on growing and developing careers and promoting from within.
Safeguarding the health and safety of our employees is a top priority.
1 unchanged sentence
Our cross-functional safety committee meets regularly to discuss policies and protocols, strategic planning, business continuity and other matters.
−Removed: We invest in initiatives aimed at promoting employee well-being.
+Added: We invest in initiatives aimed at promoting employee mental and physical well-being, including providing meals and access to fitness facility onsite.
To support our employees personally and professionally, we have Employee Assistance Programs to address employee challenges and needs.
+Added: We also allow for flexible working arrangements for certain of our employees.
We value feedback from our employees and use it to improve our workplace policies and practices.
4 unchanged sentences
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.